Process for preparing optically active cyclic amines

ABSTRACT

Optically active cyclic amines of the formula (I) or salts thereof in which A, R0, R are each as defined in claim 1, and R0 and A, or R and A, or R0 and R may also form rings, where R and the NH—R0 group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration, can be prepared effectively by a process, which comprises converting an imine (a racemic imine) of the formula (II) in which A, R0 and R are each as defined in formula (I), in the presence of hydrogen or a hydrogen donor and a nonenzymatic catalyst which comprises a catalytically active optically active complex of one or more transition metals from the group of ruthenium, rhodium, palladium, iridium, osmium, platinum, iron, nickel and samarium with organic ligands, to the compound of the formula (I).

The invention relates to the technical field of processes for preparing optically active intermediates which can be used for syntheses of active ingredients, for example active ingredients for crop protection compositions or medicaments.

Optically active compounds are frequently required as intermediates for the preparation of optically active active ingredients. This is true of enantioselective preparation processes in which the desired spatial structure is introduced at certain chiral centers at the stage of an intermediate and is retained up to the active ingredient through one or more process steps. Suitable intermediates are optically active natural substances or compounds in which a chiral center is obtained from achiral compounds with the aid of enantioselective reactions, or racemic compounds for which, in a selective manner, only one of the enantiomers present is converted enantioselectively and used further.

Amino compounds have great significance as intermediates for active crop protection ingredients and active medicament ingredients. Numerous processes for preparing optically active amines are known; see, for example, Angew. Chem. Int. Ed. 2004 (116) 806-843 and literature cited there. In addition to classical optical resolution via diastereomeric salts with optically active acids, some relate to the use of optically active starting materials and enantioselective conversions up to the desired compound. Other processes are based on enzymatic reactions, for example transaminations using enzymes or microorganisms. Other processes again utilize the use of synthetic optically active reagents and their properties in reactions to obtain chiral centers enantioselectively.

The known processes usually have the disadvantage that they can be employed only very specifically on certain substrates. With structurally different substrates, the results with regard to parameters such as chemical yield, enantiomeric excess, selectivity, purity, reaction time and availability of starting materials and auxiliaries are often unsatisfactory. There is therefore a need, in the specific case and also generally, for the provision of alternative processes for preparing optically active amines.

It has now been found that certain optically active cyclic amines with a second, adjacent chiral center can be prepared in a particularly effective manner enantioselectively from compounds which are present in racemic form with regard to the adjacent chiral center.

The invention provides a process for preparing optically active cyclic amines of the formula (I) and salts thereof

in which

-   A, together with the carbon atoms designated with an asterisk (*) in     each case, is a carbocyclic or heterocyclic, saturated or     unsaturated, nonaromatic ring which has from 3 to 30 ring atoms,     preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring     atoms, and may be further substituted in addition to the R and NH—R⁰     radicals, -   R⁰, independently of R, is a (C₁-C₆)alkyl, (C₂-C₆)alkenyl or     (C₃-C₆)alkynyl radical, where each of the three latter radicals may     be unsubstituted or substituted by one or more radicals selected     from the group consisting of halogen, cyano, (C₁-C₆)alkoxy,     (C₁-C₆)haloalkoxy, (C₁-C₆)alkylthio, (C₁-C₆)alkanoyloxy,     (C₁-C₆)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and     heterocyclyl, where each of the latter 5 radicals is unsubstituted     or substituted, or is     -   (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, aryl or heterocyclyl,         where each of the latter 4 radicals is unsubstituted or         substituted, -   R, independently of R⁰, is     -   (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl, where each of         the three latter radicals is unsubstituted or substituted by one         or more radicals selected from the group consisting of halogen,         cyano, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, (C₁-C₆)alkylthio, aryl         which is unsubstituted or substituted, and heteroaryl which is         unsubstituted or substituted, or     -   aryl which is unsubstituted or substituted, or is     -   heteroaryl which is unsubstituted or substituted, or -   R⁰ and A form a ring B1 and, together with the NH group and the     carbon atom which is designated with an asterisk (*) and is bonded     to the NH group, are a heterocyclic ring which has from 4 to 30 ring     atoms, preferably from 4 to 9 ring atoms, in particular from 5 to 7     ring atoms, and is optionally additionally further substituted and     which optionally contains 1 or 2 further heteroatoms from the group     of N, O and S, or -   R and A form a ring B2 and, together with the carbon atom which is     designated with an asterisk (*) and is bonded to R, are a     carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms,     preferably from 4 to 9 ring atoms, in particular from 5 to 7 ring     atoms, and is optionally additionally further substituted, and     which, in the case of a heterocyclic ring, contains 1, 2 or 3     heteroatoms from the group of N, O and S, or -   R⁰ and R form a ring B3 and, together with the NH group and the     carbon atoms designated with an asterisk (*) in each case, are a     heterocyclic ring which has from 4 to 30 ring atoms, preferably from     4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is     optionally additionally further substituted and which optionally     contains 1 or 2 further heteroatoms from the group of N, O and S, or -   R⁰ and R and, if appropriate, A may simultaneously form two or more     of the rings B1, B2 and B3 mentioned,     where R and the NH—R⁰ group on the two ring carbon atoms marked with     an asterisk (*) in each case are arranged in cis arrangement to one     another and the stereochemical configuration on these carbon atoms     is different from the racemic configuration,     which comprises converting an imine of the formula (II) or a salt     thereof

-   -   where A, R⁰ and R are each as defined in formula (I) and the         compound of the formula (II), with regard to the ring carbon         atom marked with an asterisk (*), is present in the form of a         racemic mixture or in the form of a mixture with any other         isomeric ratio of the stereoisomers in question,         in the presence of hydrogen or a hydrogen donor and a         nonenzymatic catalyst which comprises a catalytically active         optically active complex of one or more transition metals from         the group of ruthenium, rhodium, palladium, iridium, osmium,         platinum, iron, nickel and samarium, preferably one or more         transition metals from the group of ruthenium, rhodium,         palladium and iridium, especially ruthenium and iridium, with         organic ligands, to the compound of the formula (I) or its salt.

The absolute configuration of the product depends in the individual case upon the structure of the optically active catalyst from the group of catalysts mentioned.

Compounds of the formula (I) are especially the compounds of the formulae (I-A) and (I-B)

in which A, R⁰ and R are each as defined above. According to the Cahn-Ingold-Prelog stereochemical nomenclature, the compound (I-A) has, according to the sequence of the substituents on the carbon atom 1, the stereochemical designation (1S-cis) or (1R-cis). The compound (I-B) correspondingly has the stereochemical designation (1R-cis) or (1S-cis).

The compounds (I) with cis configuration on the two chiral centers designated with an asterisk (*) in each case are preferably obtained with a selectivity of from 60 to 100%, preferably from 80 to 100%, in particular from 90 to 100%, very particularly from 95 to 100% in comparison to the trans configuration, the particular cis compound (I-A) or (I-B) being obtained with an enantioselectivity of in each case more than 20% ee or better more than 50% ee, preferably from 60 to 100% ee, in particular from 80 to 100% ee, very particularly from 90 to 100% ee, most preferably from 95 to 100% ee, based on the total content of cis compounds (I-A) and (I-B) in question.

The enantiomeric excess measured in % ee means the difference of the percentages of the two enantiomers based on the mixture of the enantiomers.

The particular compound of the formula (II) consists generally of a mixture of the compounds (II-A1), (II-A2), (II-B1) and (II-B2)

the compounds (II-A1) and (II-A2) being designated together for short as compounds (II-A), and the compounds (II-B1) and (II-B2) being designated together for short as compounds (II-B). The compounds (II-A) and (II-B) may be used generally in any ratio with regard to the configuration on the carbon atom 2. In general, they are present in this regard preferably in the ratio of 1:1, i.e. in a racemic mixture.

The compounds (II-A1) and (II-A2) or (II-B1) and (II-B2) are usually present in equilibrium under the reaction conditions.

When the compounds (I) or (II) can form tautomers by shifting of hydrogen, which would structurally not be covered by the formula (I) or (II) in a formal sense, these tautomers are equally encompassed by the definition of the inventive compounds of the formula (I) or (II).

The compounds of the general formula (I) (or, correspondingly, other inventive compounds) may, depending on the type and attachment of the substituents, contain further chiral centers than the carbon atoms marked with an asterisk (*) in formula (I) and are correspondingly present in the form of stereoisomers. The possible stereoisomers defined by their specific three-dimensional form, such as enantiomers, diastereomers, Z and E isomers, are all encompassed by the formula (I). When, for example, one or more alkenyl groups are present, diastereomers (Z and E isomers) can occur. When, for example, one or more asymmetric carbon atoms are present, enantiomers and diastereomers can occur. Stereoisomers can be obtained from the mixtures obtained in the preparation by customary separation methods, for example by chromatographic separation processes. It is likewise possible to selectively prepare stereoisomers by use of stereoselective reactions using optically active starting materials and/or assistants. The invention thus also relates to all stereoisomers which are encompassed by the general formula (I) but are not specified with their specific stereochemical form, and mixtures thereof.

The possible combinations of the different substituents of the general formula (I) are to be understood such that the general principles of constructing chemical compounds are to be observed, i.e. the formula (I) does not encompass compounds which are known by the skilled worker to be chemically impossible.

The compounds of the formula (I) can form salts, for example by addition of a suitable inorganic or organic acid, for example mineral acids, for example HCl, HBr, H₂SO₄ or HNO₃, or organic acids such as formic acid, acetic acid, propionic acid, oxalic acid or sulfonic acids, to a basic group, for example the amino group present or other amino groups, alkylamino, dialkylamino, piperidino, morpholino or pyridino. These salts then contain the conjugate base of the acid as an ion.

Salts can be formed by the action of a base on those compounds of the formula (I) which bear an acidic hydrogen atom. Suitable bases are, for example, organic amines, and also the hydroxides, carbonates and hydrogencarbonates of ammonium, alkali metals or alkaline earth metals, especially the hydroxide, carbonate and hydrogencarbonate of sodium and potassium. These salts are compounds in which the acidic hydrogen is replaced by a cation, for example metal salts, especially alkali metal salts or alkaline earth metal salts, especially sodium and potassium salts, or else ammonium salts, salts with organic amines or quaternary ammonium salts.

Suitable substituents which are present in deprotonated form, for example sulfonic acids or carboxylic acids, may form internal salts with groups which are themselves protonatable, such as amido groups.

The compounds of the formula (I) and their salts are also referred to below for short as “compounds (I) used in accordance with the invention” or inventive “compounds (I)”.

The terms above and used below are familiar to those skilled in the art and have in particular the definitions explained below:

An inorganic radical is a radical without carbon atoms, preferably halogen, OH and its inorganic salts in which the H is replaced by a cation, for example alkali metal and alkaline earth metal salts, NH₂ and its ammonium salts with (inorganic) acids, for example mineral acids, N₃ (azide), N₂ ⁺A⁻ (diazonium radical where A⁻ is an anion), NO, NHOH, NHNH₂, NO₂, S(O)OH (sulfinic acid radical), S(O)₂OH (or else SO₃H for short, sulfonic acid radical), —O—SO₂H (sulfite), —O—SO₃H (sulfate), —P(O)(OH)₂ (phosphonic acid radical), —O—P(OH)₃ (phosphate radical), and the hydrated or dehydrated forms of the latter 6 acid radicals and also their (inorganic) salts; the term “inorganic radical” also encompasses the hydrogen radical (the hydrogen atom), the latter often already being part of the unsubstituted basic structure of an organic radical in these definitions (example: “unsubstituted phenyl”); the term “inorganic radical” here preferably does not encompass pseudohalogen groups such as CN, SCN, organic metal complexes, carbonate or COOH, which can be assigned more appropriately to the organic radicals owing to the content of carbon atoms.

In contrast to an inorganic radical, an organic radical is a radical with carbon atoms, and this radical may also be bonded via heteroatoms. It is preferably an optionally substituted hydrocarbon radical or an optionally substituted heterocyclic radical. However, it preferably also encompasses acyl radicals, i.e. radicals of organic acids which are formed by removal of an OH group. Acyl radicals also include sulfonic ester groups, phosphonic ester groups, phosphinic ester groups, each with organic alcohol components (and are then derived from polybasic acids), or alkylsulfonyl or alkylsulfinyl which are derived from sulfonic acids or sulfinic acids.

A hydrocarbon radical is an aliphatic, cycloaliphatic or aromatic monocyclic radical or, in the case of an optionally substituted hydrocarbon radical, also a bicyclic or polycyclic organic radical based on the elements carbon and hydrogen, for example encompassing the radicals alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, phenyl, naphthyl, indanyl, indenyl, etc; the same applies to the hydrocarbonoxy radicals. Unless defined more specifically, the hydrocarbon and hydrocarbonoxy radicals in the above definitions have preferably from 1 to 20 carbon atoms, more preferably from 1 to 16 carbon atoms, in particular from 1 to 12 carbon atoms.

The hydrocarbon radicals and the more specific alkyl, alkoxy, haloalkyl, haloalkoxy, alkylamino and alkylthio radicals, and also the corresponding unsaturated and/or substituted radicals may each be straight-chain or branched in the carbon skeleton.

The expression “(C₁-C₄)alkyl” means a short notation for open-chain alkyl having from one to 4 carbon atoms in accordance with the range specification for carbon atoms, i.e. encompasses the methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-butyl, 2-methylpropyl or tert-butyl radicals. General alkyl radicals with a larger specified range of carbon atoms, for example “(C₁-C₆)alkyl”, correspondingly also encompass straight-chain or branched alkyl radicals having a larger number of carbon atoms, i.e. in the example also the alkyl radicals with 5 and 6 carbon atoms. Unless stated specifically, preference is given in the case of hydrocarbon radicals such as alkyl, alkenyl and alkynyl radicals, including in combined radicals, to the lower carbon structures, for example with from 1 to 6 carbon atoms, in particular from 1 to 4 carbon atoms, or, in the case of unsaturated groups, having from 2 to 6 carbon atoms, in particular 2-4 carbon atoms. Alkyl radicals, including in the combined definitions such as alkoxy, haloalkyl, etc., are, for example, methyl, ethyl, n- or i-propyl, n-, i-, t- or 2-butyl, pentyls, hexyls such as n-hexyl, i-hexyl and 1,3-dimethylbutyl, heptyls such as n-heptyl, 1-methylhexyl and 1,4-dimethylpentyl; alkenyl and alkynyl radicals have the definition of the possible unsaturated radicals corresponding to the alkyl radicals; alkenyl is, for example, vinyl, allyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 2-butenyl, pentenyl, 2-methylpentenyl or hexenyl, preferably allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl or 1-methylbut-2-en-1-yl. (C₂-C₆)Alkynyl is, for example, ethynyl, propargyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl, 2-butynyl, 2-pentynyl or 2-hexynyl, preferably propargyl, but-2-yn-1-yl, but-3-yn-1-yl or 1-methyl-but-3-yn-1-yl.

Alkylidene, for example including in the form of (C₁-C₁₀)alkylidene, is the radical of a straight-chain or branched alkane which is bonded via a double bond, the position of the bonding site not having been specified. In the case of a branched alkane, by its nature, only positions at which two hydrogen atoms can be replaced by the double bond are possible; radicals are, for example, ═CH₂, ═CH—CH₃, ═C(CH₃)—CH₃, ═C(CH₃)—C₂H₅ or ═C(C₂H₅)—C₂H₅.

Cycloalkyl is a carbocyclic, saturated ring system having preferably 3-8 carbon atoms, for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Substituted cycloalkyl encompasses cyclic systems with substituents, also encompassing substituents with a double bond on the cycloalkyl radical, for example an alkylidene group such as methylidene. Substituted cycloalkyl also encompasses polycyclic aliphatic systems, for example bicyclo[1.1.0]butan-1-yl, bicyclo[1.1.0]butan-2-yl, bicyclo[2.1.0]pentan-1-yl, bicyclo[2.1.0]pentan-2-yl, bicyclo[2.1.0]pentan-5-yl, adamantan-1-yl and adamantan-2-yl.

Cycloalkenyl is a carbocyclic, nonaromatic, partially unsaturated ring system having preferably 4-8 carbon atoms, for example 1-cyclobutenyl, 2-cyclobutenyl, 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, or 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1,3-cyclohexadienyl or 1,4-cyclohexadienyl. In the case of substituted cycloalkenyl, the explanations for substituted cycloalkyl apply correspondingly. In particular, substituted cycloalkenyl also encompasses corresponding fused polycyclic compounds, for example benzofused compounds such as tetrahydronaphthalin-1-yl or -2-yl, fluorenyl(biphenylmethyl) or suberyl(di-[b,f]-benzocyclohepta-2,6-dien-1-yl).

The term “halogen” means, for example, fluorine, chlorine, bromine or iodine. Haloalkyl, -alkenyl and -alkynyl mean alkyl, alkenyl and alkynyl substituted partly or fully by identical or different halogen atoms, preferably form the group of fluorine, chlorine and bromine, especially from the group of fluorine and chlorine, for example monohaloalkyl such as CH₂CH₂Cl, CH₂CH₂F, CH₂ClCH₃, CH₂FCH₃, CH₂Cl, CH₂F; perhaloalkyl such as CCl₃ or CF₃ or CF₃CF₂; polyhaloalkyl such as CHF₂, CH₂F, CH₂FCHCl, CHCl₂, CF₂CF₂H, CH₂CF₃, CH₂ClCH₃, CH₂FCH₃; haloalkoxy is, for example, OCF₃, OCHF₂, OCH₂F, CF₃CF₂O, OCH₂CF₃ and OCH₂CH₂Cl; the same applies to haloalkenyl and other radicals substituted by halogen.

Aryl is a mono-, bi- or polycyclic aromatic system having preferably from 6 to 14, in particular from 6 to 12 carbon atoms, for example phenyl, naphthyl, tetrahydronaphthyl, indenyl, indanyl, pentalenyl, fluorenyl, biphenylyl and the like, preferably phenyl.

A heterocyclic radical or ring (heterocyclyl) contains at least one heterocyclic ring which is saturated, unsaturated or heteroaromatic and which may be fused in the generally substituted case with other carbocyclic or heterocyclic rings; unless defined differently, the heterocyclic ring contains preferably from 3 to 9 ring atoms, in particular from 3 to 6 ring atoms, and one or more, preferably from 1 to 4, in particular 1, 2 or 3 heteroatoms in the heterocyclic ring, preferably from the group of N, O and S, although two oxygen atoms should not be directly adjacent and at least one carbon atom also has to be present in the ring, for example a radical of thiophene, furan, pyrrole, thiazole, oxazole, imidazole, isothiazole, isoxazole, pyrazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole, 1,3,4-triazole, 1,2,4-oxadiazole, 1,2,4-thiadiazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,3,4-tetrazole, benzo[b]thiophene, benzo[b]furan, indole, benzo[c]thiophene, benzo[c]furan, isoindole, benzoxazole, benzothiazole, benzimidazole, benzisoxazole, benzisothiazole, benzopyrazole, benzothiadiazole, benzotriazole, dibenzofuran, dibenzothiophene, carbazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,4,5-tetrazine, quinoline, isoquinoline, quinoxaline, quinazoline, quinoline, 1,8-naphthyridine, 1,5-naphthyridine, 1,6-naphthyridine, 1,7-naphthyridine, phthalazine, pyridopyrimidine, purine, pteridine, 4H-quinolizine, piperidine, morpholine, piperazine, oxetane, oxirane, pyrrolidine, oxazoline, tetrahydrofuran, tetrahydropyran, 1,3-dioxolane, 1,3- and 1,4-dioxane, isoxazolidine or thiazolidine.

Among the groups mentioned above under “heterocyclyl”, “heteroaryl” in each case means the fully unsaturated aromatic heterocyclic compounds, for example pyridine, pyrimidine, (1,2,4)-oxadiazole, (1,3,4)-oxadiazole, pyrrole, furan, thiophene, oxazole, Thiazole, imidazole, pyrazole, isoxazole, 1,2,4-triazole, tetrazole, pyrazine or pyridazine.

Preference is further given to heterocyclyl being a partially or fully hydrogenated heterocyclic radical having a heteroatom from the group of N, O and S, for example oxiranyl, oxetanyl, oxolanyl(=tetrahydrofuryl), oxanyl, pyrrolinyl, pyrrolidinyl or piperidinyl.

Preference is further given to it being a partially or fully hydrogenated heterocyclic radical having 2 heteroatoms from the group of N, O and S, for example oxazolinyl, thiazolinyl, piperazinyl, 1,3-dioxolanyl, 1,3- and 1,4-dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl and morpholinyl.

When it is a partly or fully saturated nitrogen heterocycle, it may be bonded to the radical of the molecule of the particular compound either via carbon or via the nitrogen.

Heterocyclyl is preferably an aliphatic, saturated or unsaturated, especially saturated, heterocyclyl radical having from 3 to 7, in particular from 3 to 6 ring atoms, or a heteroaromatic radical having 5 or 6 ring atoms. Heterocyclyl preferably contains heterocyclic ring atoms from the group of N, O and S.

Preferred examples of heterocyclyl are a heterocyclic radical having from 3 to 6 ring atoms from the group of pyridyl, thienyl, furyl, pyrrolyl, oxiranyl, 2-oxetanyl, 3-oxetanyl, oxolanyl (=tetrahydrofuryl), pyrrolidinyl, piperidinyl, in particular oxiranyl, 2-oxetanyl, 3-oxetanyl or oxolanyl, or a heterocyclic radical having two or three heteroatoms, for example pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, thienyl, thiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, pyrazolyl, triazolyl, piperazinyl, dioxolanyl, dioxanyl, oxazolinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl or morpholinyl.

When a basic structure is substituted “by one or more radicals” from a list of radicals (=group) or a generically defined group of radicals, this in each case includes the simultaneous substitution by a plurality of identical and/or structurally different radicals.

In the case of a plurality of optionally substituted basic structures, the definition “where each of the latter radicals (=basic structures) is unsubstituted or substituted” means that each of the radicals (=basic structures) is unsubstituted or substituted independently of the other radicals.

Possible substituents for a substituted heterocyclic radical include the substituents mentioned below, and additionally also oxo. The oxo group as a substituent then means, for example, a carbonyl group in the heterocyclic ring. Thus, lactones and lactams are preferably also encompassed. The oxo group may also occur on the heterocyclic ring atoms which can exist in various oxidation states, for example in the case of N and S, and in that case form, for example, the divalent groups —N(O)—, —S(O)— (also SO for short) and —S(O)₂— (also SO₂ for short) in the heterocyclic ring.

Substituted radicals such as a substituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, phenyl, benzyl, heterocyclyl and heteroaryl radical, are, for example, a substituted radical derived from the unsubstituted basic structure, the substituents being, for example, one or more, preferably 1, 2 or 3 radicals from the group of halogen, alkoxy, alkylthio, hydroxy, amino, nitro, carboxy, cyano, azido, alkoxycarbonyl, alkanoyl, alkoxycarbonyloxy, alkanoyloxy, aryloxycarbonyl, aryloxycarbonyloxy, carbamoyl, mono- and dialkylaminocarbonyl, substituted amino such as acylamino, mono- and dialkylamino, trialkylsilyl and optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heterocyclyl, where each of the latter cyclic groups may also be bonded via heteroatoms or divalent functional groups as in the case of the alkyl radicals mentioned, and alkylsulfinyl, alkylsulfonyl, and, in the case of cyclic radicals (=“cyclic basic structures”), also alkyl, haloalkyl, alkylthioalkyl, alkoxyalkyl, optionally substituted mono- and dialkylaminoalkyl and hydroxyalkyl; in the term “substituted radicals” such as substituted alkyl, etc., included as substituents in addition to the saturated hydrocarbon-containing radicals mentioned are corresponding unsaturated aliphatic and aromatic radicals such as optionally substituted alkenyl, alkynyl, alkenyloxy, alkynyloxy, phenyl, phenoxy, etc.

Substituted cyclic radicals with aliphatic moieties in the ring also encompass cyclic systems with such substituents which are bonded to the ring with a double bond, for example with an alkylidene group such as methylidene or ethylidene, or an oxo group, imino group or substituted imino group.

The substituents mentioned by way of example (“first substituent level”) may, when they contain hydrocarbon-containing moieties, optionally further be substituted there (“second substituent level”), for example by one of the substituents as defined for the first substituent level. Corresponding further substituent levels are possible. The term “substituted radical” preferably encompasses only one or two substituent levels.

Preferred substituents for the substituent levels are, for example, amino, hydroxy, halogen, nitro, cyano, mercapto, carboxy, carbonamide, SF₅, aminosulfonyl, alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, monoalkylamino, dialkylamino, N-alkanoylamino, alkoxy, alkenyloxy, alkynyloxy, cycloalkoxy, cycloalkenyloxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, aryloxycarbonyl, alkanoyl, alkenylcarbonyl, alkynylcarbonyl, arylcarbonyl, arylcarbonyloxy, alkanoyloxy, alkenylcarbonyloxy, alkynylcarbonyloxy, alkoxycarbonyloxy, alkenyloxycarbonyloxy, alkynyloxycarbonyloxy, aryloxycarbonyloxy, alkylthio, cycloalkylthio, alkenylthio, cycloalkenylthio, alkynylthio, alkylsulfinyl, alkylsulfonyl, monoalkylaminosulfonyl, dialkylaminosulfonyl, N-alkylaminocarbonyl, N,N-dialkylaminocarbonyl, N-alkanoylaminocarbonyl, N-alkanoyl-N-alkyl-aminocarbonyl, aryl, aryloxy, benzyl, benzyloxy, benzylthio, arylthio, arylamino, benzylamino, heterocyclyl and trialkylsilyl.

In the case of radicals with carbon atoms, preference is given to those having from 1 to 6 carbon atoms, preferably from 1 to 4 carbon atoms, in particular 1 or 2 carbon atoms. Preference is generally given to substituents from the group of halogen, e.g. fluorine or chlorine (C₁-C₄)alkyl, preferably methyl or ethyl, (C₁-C₄)haloalkyl, preferably trifluoromethyl, (C₁-C₄)alkoxy, preferably methoxy or ethoxy, (C₁-C₄)haloalkoxy, nitro and cyano. Particular preference is given to the substituents methyl, methoxy, fluorine and chlorine.

Substituted amino such as mono- or disubstituted amino is a radical from the group of the substituted amino radicals which is n-substituted, for example, by one or two identical or different radicals from the group of alkyl, alkoxy, acyl and aryl; preferably mono- and dialkylamino, mono- and diarylamino, acylamino, N-alkyl-N-arylamino, N-alkyl-N-acylamino, and also saturated H-heterocycles; preference is given to alkyl radicals having from 1 to 4 carbon atoms; aryl is preferably phenyl or substituted phenyl; for acyl, the definition specified below applies, preferably (C₁-C₄)alkanoyl. The same applies to substituted hydroxylamino or hydrazino.

Optionally substituted phenyl is preferably phenyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy and nitro, for example o-, m- and p-tolyl, dimethylphenyls, 2-, 3- and 4-chlorophenyl, 2-, 3- and 4-fluorophenyl, 2-, 3- and 4-trifluoromethyl- and -trichloromethylphenyl, 2,4-, 3,5-, 2,5- and 2,3-dichlorophenyl, o-, m- and p-methoxyphenyl.

Optionally substituted cycloalkyl is preferably cycloalkyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl and (C₁-C₄)haloalkoxy, especially by one or two (C₁-C₄)alkyl radicals.

Optionally substituted heterocyclyl is preferably heterocyclyl which is unsubstituted or mono- or polysubstituted, preferably up to trisubstituted, by identical or different radicals from the group of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy, nitro and oxo, especially mono- or polysubstituted by radicals from the group of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl and oxo, very particularly by one or two (C₁-C₄)alkyl radicals.

Acyl is a radical of an organic acid which is formed, in a formal sense, by removing a hydroxyl group at the acid function, and the organic radical in the acid may also be bonded with the acid function via a heteroatom. Examples of acyl are the —CO—R radical of a carboxylic acid HO—CO—R and radicals of acids derived therefrom, such as of thiocarboxylic acid, optionally N-substituted iminocarboxylic acids, or the radical of carbonic monoesters, N-substituted carbamic acid, sulfonic acids, sulfinic acids, N-substituted sulfonamide acids, phosphonic acids, phosphinic acids.

Acyl is, for example, alkanoyl such as formyl or [(C₁-C₄)alkyl]carbonyl, phenylcarbonyl, alkyloxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl, alkylsulfonyl, alkylsulfinyl, N-alkyl-1-iminoalkyl, N-alkyl- and N,N-dialkylcarbamoyl and other radicals of organic acids. The radicals may each be further substituted in the alkyl or phenyl moiety, for example in the alkyl moiety by one or more radicals from the group of halogen, alkoxy, phenyl and phenoxy; examples of substituents in the phenyl moiety are the substituents already mentioned above in general for substituted phenyl.

Acyl is preferably an acyl radical in the narrower sense, i.e. a radical of an organic acid in which the acid group is bonded directly to the carbon atom of an organic radical, for example alkanoyl such as formyl and acetyl, aroyl such as phenylcarbonyl, and other radicals of saturated or unsaturated organic acids.

“Aroyl” is an aryl radical as defined above which is bonded via a carbonyl group, for example the benzoyl group.

When a general radical is defined as hydrogen, this means a hydrogen atom.

“yl position” of a radical designates its binding site.

For reasons of better preparability, especially with regard to yield, space-time yield, enantioselectivity of the process and simplicity of the process, but also for reasons of usability, closer interest attaches to inventive processes for preparing amino compounds of the formula (I) in which

-   A, together with the carbon atoms designated with an asterisk (*) in     each case, is a carbocyclic or heterocyclic, saturated or     unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in     particular from 5 to 7 ring atoms, and, in addition to the R and     NH—R⁰ radicals, is unsubstituted or further substituted by one or     more radicals selected from the group consisting of halogen,     hydroxy, amino, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₉)cycloalkyl,     (C₂-C₄)alkenyl, (C₅-C₉)cycloalkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,     (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfonyl, aryl     and heterocyclyl, where the latter 11 radicals are each     independently unsubstituted or substituted by one or more radicals     selected from the group consisting of halogen, cyano,     (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, (C₁-C₄)alkoxy,     (C₁-C₄)alkylthio and, in the case of cyclic radicals, also     (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, and is optionally substituted by     a fused carbocyclic or heterocyclic ring which has from 3 to 30 ring     atoms and, in the case of a heterocyclic ring, contains from 1 to 3     ring atoms from the group of N, O and S, and is optionally further     substituted by one or more radicals selected from the group     consisting of halogen, cyano, (C₁-C₄)alkyl, (C₃-C₉)cycloalkyl,     (C₂-C₄)alkenyl, (C₅-C₉)cycloalkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy     and (C₁-C₄)alkylthio, where each of the latter 7 radicals is     independently unsubstituted or substituted by one or more radicals     selected from the group consisting of halogen, cyano,     (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, (C₁-C₄)alkoxy,     (C₁-C₄)alkylthio and, in the case of cyclic radicals, also     (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, -   R⁰, independently of R, is a (C₁-C₆)alkyl, (C₂-C₆)alkenyl or     (C₃-C₆)alkynyl radical, where each of the three latter radicals is     unsubstituted or substituted by one or more radicals selected from     the group consisting of halogen, cyano, (C₁-C₄)alkoxy,     (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkanoyloxy,     (C₁-C₄)haloalkanoyloxy, phenyl which is unsubstituted or substituted     and heterocyclyl which is unsubstituted or substituted,     -   or (C₃-C₉)cycloalkyl which is unsubstituted or substituted,         preferably unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, cyano,         (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio and phenyl which is         unsubstituted or substituted,     -   or (C₄-C₉)cycloalkenyl which is unsubstituted or substituted,         preferably unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, cyano,         (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio and phenyl which is         unsubstituted or substituted, and is optionally fused,         preferably benzofused, at one or more double bonds in the ring         with an aromatic ring which does or does not have further         substitution,     -   or phenyl which is unsubstituted or substituted, preferably         unsubstituted or substituted by one or more radicals selected         from the group consisting of halogen, cyano, (C₁-C₄)alkyl,         (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,         (C₁-C₄)alkylthio and phenyl which is unsubstituted or         substituted, and is optionally fused, preferably benzofused, at         one or more double bonds in the ring with an aromatic ring which         does or does not have further substitution,     -   or heterocyclyl which is unsubstituted or substituted,         preferably unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, cyano,         (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio and phenyl which is         unsubstituted or substituted, and is optionally, in the case of         an unsaturated or heteroaromatic heterocyclyl, fused, preferably         benzofused, at one or more double bonds in the ring which does         or does not have further substitution, or     -   R⁰ is in particular an eliminable radical (cleavable group,         leaving group) selected from the group consisting of     -   i) CH₂C₆H₅ (benzyl)     -   ii) CH₂CH═CH₂ (allyl)     -   iii) C(CH₃)₃ (t-butyl)     -   iv) C(C₆H₅)₃ (trityl)     -   v) CH₃ (methyl)     -   vi) (CH₂)₃OCOCH₃ (3-acetoxypropyl)     -   vii) CH₂C₆H₃-2,4-(OCH₃)₂ (2,4-dimethoxybenzyl)     -   viii) C₆H₃-2,4-(NO₂)₂ (2,4-dinitrophenyl)     -   ix) CH₂C₆H₄-4-OCH₃ (4-methoxybenzyl)     -   x) CH₂C₆H₄-2-OH (2-hydroxybenzyl)     -   xi) CH(C₆H₅)₂ (diphenylmethyl)     -   xii) CH(C₆H₄-4-OCH₃)₂ (bis-(4-methoxyphenyl)methyl)     -   xiii) C(C₆H₅)₂(C₆H₄₄—OCH₃) (4-methoxyphenyl)diphenylmethyl)     -   xiv) 5-Dibenzosuberyl(dibenzo-[b,f]-cyclohepta-2,6-dien-1-yl)     -   xv) 9-Phenylfluoren-9-yl (1-phenyldiphenylenemethyl),     -   where each of the phenyl or heterocyclyl radicals mentioned,         which is unsubstituted or substituted (i.e. is optionally         substituted without specification of the substituents), is         preferably unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, cyano, nitro,         (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl,         (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy(C₁-C₄)haloalkoxy,         (C₁-C₄)alkoxy-(C₁-C₄)alkyloxy, (C₁-C₄)alkylthio,         (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkanoyl,         [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylamino and         di[(C₁-C₄)alkyl]amino; in particular, each of the phenyl or         heterocyclyl radicals mentioned which is unsubstituted or         substituted is preferably unsubstituted or substituted by one or         more radicals selected from the group consisting of halogen,         (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkyl, (C₁-C₄)haloalkoxy         and nitro, -   R, independently of R⁰, is     -   (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl, where each of         the three latter radicals is unsubstituted or substituted by one         or more radicals selected from the group consisting of halogen,         cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, aryl         which is optionally substituted and heteroaryl which is         optionally substituted, or     -   aryl which is optionally substituted, or     -   heteroaryl which is optionally substituted,         -   where the optionally substituted radicals are each             independently preferably unsubstituted or substituted by one             or more radicals selected from the group consisting of             halogen, hydroxy, amino, cyano, nitro, (C₁-C₄)alkyl,             (C₃-C₉)cycloalkyl, (C₂-C₄)alkenyl, (C₅-C₉)cycloalkenyl,             (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₅)alkanoyl,             [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylthio,             (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkylamino,             di-(C₁-C₄)alkylamino, aryl and heterocyclyl, where the             latter 14 radicals are each independently unsubstituted or             substituted by one or more radicals selected from the group             consisting of halogen, cyano, (C₃-C₉)cycloalkyl,             (C₅-C₉)cycloalkenyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and, in             the case of cyclic radicals, also (C₁-C₄)alkyl and             (C₁-C₄)haloalkyl, or -   R⁰ and A form a ring B1 and, together with the NH group and the     carbon atom which is designated with an asterisk (*) and is bonded     to the NH group, are a heterocyclic ring having from 4 to 30 ring     atoms, preferably having from 4 to 9 ring atoms, in particular     having from 5 to 7 ring atoms, which is optionally additionally     further substituted and which optionally contains one or more     further heteroatoms from the group of N, O and S,     -   and are preferably the heterocyclic ring mentioned which does         not have further substitution or is substituted by one or more         radicals selected from the group consisting of halogen, hydroxy,         amino, cyano, nitro, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl,         (C₃-C₉)cycloalkyl, (C₂-C₄)alkenyl, (C₅-C₉)cycloalkenyl,         (C₂-C₄)alkynyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,         (C₁-C₄)alkylthio and (C₁-C₄)alkylsulfonyl, or -   R and A form a ring B2 and, together with the carbon atom which is     designated with an asterisk (*) and bonded to R, form a carbocyclic     or heterocyclic ring which has from 3 to 30 ring atoms, preferably     from 3 to 9 ring atoms, in particular from 4 to 7 ring atoms, and     may optionally additionally be further substituted and, in the case     of a heterocyclic ring, contains 1 or 2 or 3 further heteroatoms     selected from the group consisting of N, O and S,     -   and are preferably the carbocyclic or heterocyclic ring         mentioned which may not have further substitution or may have         further substitution by one or more radicals selected from the         group consisting of halogen, hydroxy, amino, cyano, nitro,         (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, (C₃-C₉)cycloalkyl,         (C₂-C₄)alkenyl, (C₅-C₉)cycloalkenyl, (C₂-C₄)alkynyl,         (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio and         (C₁-C₄)alkylsulfonyl, or -   R⁰ and R form a ring B3 and, together with the NH group and the     carbon atoms designated with an asterisk (*) in each case, are a     heterocyclic ring which has from 4 to 30 ring atoms, preferably from     4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and is     optionally additionally further substituted and optionally contains     1 or 2 further heteroatoms from the group of N, O and S,     -   and are preferably the heterocyclic ring mentioned which may not         have further substitution or may have further substitution by         one or more radicals selected from the group consisting of         halogen, hydroxy, amino, cyano, nitro, (C₁-C₄)alkyl,         (C₁-C₄)haloalkyl, (C₃-C₉)cycloalkyl, (C₂-C₄)alkenyl,         (C₅-C₉)cycloalkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio and (C₁-C₄)alkylsulfonyl, or -   R⁰ and R and, if appropriate, A simultaneously form two or more of     the rings B1, B2 and B3 mentioned,     where R and the NH—R⁰ group on the two ring carbon atoms marked with     an asterisk (*) in each case are arranged in cis arrangement to one     another and the stereochemical configuration on these carbon atoms     is different from the racemic configuration.

Preferred inventive processes relate, for example, to the preparation of monocyclic compounds of the formula (Ia)

where

-   A, together with the carbon atoms designated with an asterisk (*) in     each case, is a carbocyclic or heterocyclic, saturated or     unsaturated, nonaromatic ring having from 3 to 30 ring atoms,     preferably having from 4 to 9 ring atoms, in particular having from     5 to 7 ring atoms, and, in the case of a heterocyclic ring which has     from 1 to 3 heterocyclic ring atoms selected from the group     consisting of N, O and S and, in addition to the R¹ and NH—R⁰     radicals is unsubstituted or further substituted by one or more     radicals selected from the group consisting of halogen, hydroxy,     amino, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy,     (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfonyl, aryl     and heterocyclyl, where each of the latter 8 radicals is     unsubstituted or substituted by one or more radicals selected from     the group consisting of halogen, cyano, (C₃-C₉)cycloalkyl,     (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and, in the case of cyclic radicals,     also (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, -   R⁰, independently of R¹, is as defined above in formula (I),     preferably as defined with preference for formula (I) and in     particular a (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₃-C₆)alkynyl radical,     -   where each of the three latter radicals is unsubstituted or         substituted by one or more radicals selected from the group         consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,         (C₁-C₄)alkylthio, (C₁-C₄)alkanoyloxy, (C₁-C₄)haloalkanoyloxy and         phenyl which is unsubstituted or substituted by one or more         radicals selected from the group consisting of halogen, cyano,         nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,         (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkoxy-(C₁-C₄)alkoxy,         (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,         (C₁-C₄)-alkanoyl, [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylamino and         di[(C₁-C₄)alkyl]-amino, and     -   heterocyclyl which is unsubstituted or substituted by one or         more radicals selected from the group consisting of halogen,         cyano, nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,         (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkoxy-(C₁-C₄)alkoxy,         (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,         (C₁-C₄)-alkanoyl, [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylamino and         di[(C₁-C₄)alkyl]-amino,     -   or (C₃-C₆)cycloalkyl, phenyl or heterocyclyl, where each of the         3 latter radicals is optionally substituted,     -   or, for example, one of the abovementioned eliminable         radicals i) to xiii), -   R¹, independently of R⁰, is     -   (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl, where each of         the three latter radicals is unsubstituted or substituted by one         or more radicals selected from the group consisting of halogen,         cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy and (C₁-C₄)alkylthio,     -   or aryl or heterocyclyl, where each of the 2 latter radicals is         unsubstituted or substituted, preferably unsubstituted or         substituted as in R in formula (I) for optionally substituted         phenyl or heterocyclyl, in particular by one or more radicals         selected from the group consisting of halogen, (C₁-C₄)alkyl,         (C₁-C₄)haloalkyl and (C₁-C₄)haloalkoxy,         where the substituents R¹ and the amino group on the two ring         carbon atoms marked with an asterisk (*) in each case are         arranged in cis arrangement to one another and the compound (Ia)         is present in the form of a stereochemically pure compound of         the formula (Ia-A) or (Ia-B)

in which the general radicals are as defined in formula (Ia), or in the form of an isomer mixture of the compounds of the formulae (Ia-A) and (Ia-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ib)

in which

-   A¹ is a direct bond or a group of the formula (CR⁶R⁷)_(n) in which n     is from 1 to 6 and R⁶ and R⁷ are each independently, or, in the case     that n is greater than 1, the R⁶ and R radicals are in each case     independently hydrogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, halogen,     (C₁-C₄)alkoxy or (C₁-C₄)haloalkoxy, where individual CR⁶R⁷ groups     may be replaced by heteroatoms from the group of O and S, -   R⁰ is as defined above in formula (I), preferably as defined with     preference for formula (I), and is in particular, independently of     R¹, a (C₁-C₆)alkyl or (C₂-C₆)alkenyl radical,     -   where each of the two latter radicals is unsubstituted or         substituted by one or more radicals selected from the group         consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,         (C₁-C₄)alkylthio, (C₁-C₄)alkanoyloxy, (C₁-C₄)haloalkanoyloxy and         aryl which is unsubstituted or substituted by one or more         radicals selected from the group consisting of halogen, cyano,         nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,         (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)haloalkoxy, (C₁-C₄)alkoxy-(C₁-C₄)alkoxy,         (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl,         (C₁-C₄)-alkanoyl, [(C₁-C₄)-alkoxy]-carbonyl, (C₁-C₄)alkylamino         and di-[(C₁-C₄)alkyl]-amino, and heterocyclyl which is         unsubstituted or substituted by one or more radicals selected         from the group consisting of halogen, cyano, nitro,         (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl,         (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,         (C₁-C₄)alkoxy-(C₁-C₄)alkoxy, (C₁-C₄)alkylthio,         (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, (C₁-C₄)-alkanoyl,         [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylamino and         di[(C₁-C₄)alkyl]-amino,     -   or is (C₃-C₆)cycloalkyl, phenyl or heterocyclyl, where each of         the 3 latter radicals is optionally substituted,     -   or, for example, is one of the eliminable radicals i) to xiii)         mentioned, and -   R¹, independently of R⁰, is     -   (C₁-C₆)alkyl which is unsubstituted or substituted by one or         more radicals selected from the group consisting of halogen,         cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, aryl         which is optionally substituted and heterocyclyl which is         optionally substituted, or     -   aryl which is optionally substituted or     -   heterocyclyl which is optionally substituted,     -   where the optionally substituted radicals are each independently         preferably unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, hydroxy, amino,         cyano, nitro, (C₁-C₄)alkyl, (C₃-C₉)cycloalkyl, (C₂-C₄)alkenyl,         (C₅-C₉)cycloalkenyl, (C₂-C₄)alkynyl, (C₁-C₄)alkoxy,         (C₁-C₅)alkanoyl, [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylthio,         (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkylamino, di(C₁-C₄)alkylamino,         aryl and heterocyclyl, where the latter 14 radicals are each         independently unsubstituted or substituted by one or more         radicals selected from the group consisting of halogen, cyano,         (C₃-C₉)cycloalkyl, (C₅-C₉)cycloalkenyl, (C₁-C₄)alkoxy,         (C₁-C₄)alkylthio and, in the case of cyclic radicals, also         (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, and, preferably,     -   R¹, independently of R⁰, is     -   (C₁-C₆)alkyl which is unsubstituted or substituted by one or         more radicals selected from the group consisting of halogen,         cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy and (C₁-C₄)alkylthio, or         phenyl or heterocyclyl and -   R² is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy,     (C₁-C₃)haloalkoxy or CN, -   R³ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy,     (C₁-C₃)haloalkoxy or CN, -   R⁴ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy,     (C₁-C₃)haloalkoxy or CN and -   R⁵ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy,     (C₁-C₃)haloalkoxy or CN,     where the substituents R¹ and the amino group on the two ring carbon     atoms marked with an asterisk (*) in each case are arranged in cis     arrangement to one another and the compound is present in the form     of a stereochemically pure compound of the formula (Ib-A) or (Ib-B)

in which the general radicals are each as defined in formula (Ib), or in the form of an isomer mixture of the compounds of the formulae (Ib-A) and (Ib-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ic)

in which

-   A¹ is a direct bond or a group of the formula (CR⁶R⁷)_(n) in which n     is from 1 to 6 and R⁶ and R⁷ are each independently, or, in the case     that n is greater than 1, the R⁶ and R⁷ radicals are in each case     independently hydrogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, halogen,     (C₁-C₄)alkoxy or (C₁-C₄)haloalkoxy, where individual CR⁶R⁷ groups     may be replaced by heteroatoms from the group of O and S, -   A², together with the two carbon atoms which are common with the     other ring, is a carbocyclic nonaromatic ring which has from 3 to 9     carbon atoms and is unsubstituted or substituted by one or more     radicals selected from the group consisting of (C₁-C₄)alkyl,     (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy,     hydroxy, amino and CN, -   R⁰ is as defined above in formula (I), preferably as defined with     preference for formula (I) and is in particular independently as     defined in formula (Ib), and -   R¹ is independently as defined in formula (Ib),     where the substituents R¹ and the amino group on the two ring carbon     atoms marked with an asterisk (*) in each case are arranged in cis     arrangement to one another and the compound (Ic) is present in the     form of a stereochemically pure compound of the formula (Ic-A) or     (Ic-B)

in which the general radicals are each as defined in formula (Ic), or in the form of an isomer mixture of the compounds of the formulae (Ic-A) and (Ic-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Id)

in which

-   A, together with the carbon atoms designated with an asterisk (*) in     each case, is a carbocyclic or heterocyclic, saturated or     unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in     particular from 5 to 7 ring atoms, and, in the case of a     heterocyclic ring, has from 1 to 3 heterocyclic ring atoms from the     group of N, O and S, and, in addition to the A′ and NH—R⁰ radicals,     is unsubstituted or further substituted by one or more radicals     selected from the group consisting of halogen, cyano, (C₁-C₄)alkyl,     (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy and (C₁-C₄)alkylthio, where each of     the latter 4 radicals is unsubstituted or substituted by one or more     radicals selected from the group consisting of halogen, cyano,     (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and, in the case     of cyclic radicals, also (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, and -   A′ together with the NH group and the carbon atoms designated with     an asterisk (*) in each case, is a heterocyclic ring which has from     4 to 9 ring atoms, in particular from 5 to 7 ring atoms, and     optionally contains 1 or 2 further heteroatoms from the group of N,     O and S and is unsubstituted or substituted by one or more radicals     selected from the group consisting of halogen, cyano, (C₁-C₄)alkyl,     (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio     and phenyl which is unsubstituted or substituted by one or more     radicals selected from the group consisting of halogen, cyano,     nitro, (C₁-C₄)alkyl, (C₂-C₄)alkenyl, (C₂-C₄)alkynyl,     (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy,     (C₁-C₄)haloalkoxy, (C₁-C₄)alkoxy-(C₁-C₄)alkoxy, (C₁-C₄)alkylthio,     (C₁-C₄)alkylsulfinyl, (C₁-C₄)alkylsulfonyl, (C₁-C₄)alkanoyl,     [(C₁-C₄)alkoxy]carbonyl, (C₁-C₄)alkylamino and     di[(C₁-C₄)alkyl]amino,     where the substituents A′ and the amino group on the two ring carbon     atoms marked with an asterisk (*) in each case are arranged in cis     arrangement to one another and the compound (Id) is present in the     form of a stereochemically pure compound of the formula (Id-A) or     (Id-B)

in which the general radicals are each as defined in formula (Id), or in the form of an isomer mixture of the compounds of the formulae (Id-A) and (Id-B) in an isomer ratio other than the ratio of 1:1.

Preference is also given to processes for preparing bicyclic amino compounds of the formula (Ie)

in which

-   A, together with the carbon atoms designated with an asterisk (*) in     each case, is a carbocyclic or heterocyclic, saturated or     unsaturated, nonaromatic ring which has from 4 to 9 ring atoms, in     particular from 5 to 7 ring atoms, and, in the case of a     heterocyclic ring, has from 1 to 3 heterocyclic ring atoms from the     group of N, O and S, and, in addition to the A″ and NH—R⁰ radicals,     is unsubstituted or further substituted by one or more radicals     selected from the group consisting of halogen, cyano, (C₁-C₄)alkyl,     (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy and (C₁-C₄)alkylthio, where each of     the latter 4 radicals is unsubstituted or substituted by one or more     radicals selected from the group consisting of halogen, cyano,     (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and, in the case     of cyclic radicals, also (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, and -   A″, together with the A and the carbon atom designated with “2”     (=the carbon atom which is bonded to A″ and is designated with an     asterisk), is a carbocyclic or heterocyclic ring which has from 4 to     9 ring atoms, in particular from 5 to 7 ring atoms, and, in the     heterocyclic case, contains 1 or 2 or 3 heteroatoms selected from     the group consisting of N, O and S, and is unsubstituted or     substituted by one or more radicals selected from the group     consisting of halogen, hydroxy, amino, cyano, nitro, (C₁-C₄)alkyl,     (C₁-C₄)haloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio     and phenyl which is unsubstituted or substituted by one or more     radicals from the group of halogen, cyano, nitro, (C₁-C₄)alkyl,     (C₂-C₄)alkenyl, (C₂-C₄)alkynyl, (C₁-C₄)haloalkyl,     (C₁-C₄)alkoxy-(C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy,     (C₁-C₄)alkoxy-(C₁-C₄)alkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfinyl,     (C₁-C₄)alkylsulfonyl, (C₁-C₄)-alkanoyl, [(C₁-C₄)alkoxy]-carbonyl,     (C₁-C₄)alkylamino and di[(C₁-C₄)alkyl]amino,     where R⁰ is defined independently of A″ as in the formulae (I),     (Ia), (Ib) or (Ic), and the substituents A″ and the amino group on     the two ring carbon atoms marked with an asterisk (*) in each case     are arranged in cis arrangement to one another and the compound (Ie)     is present in the form of a stereochemically pure compound of the     formula (Ie-A) or (Ie-B)

in which the general radicals are each as defined in formula (Ie), or in the form of an isomer mixture of the compounds of the formulae (Ie-A) and (Ie-B) in an isomer ratio other than the ratio of 1:1.

The reduction of the imino group of the compound (II) may be carried out analogously to processes as are known, for example, for the reduction of carbonyl compounds, or processes developed particularly therefor, as an asymmetric catalytic hydrogenation or catalytic transfer hydrogenation in the presence of hydrogen or hydrogen donors and chiral transition metal catalysts under reaction conditions under which chemical equilibrium between imine (II-A) and imine (II-B) is enabled.

Useful chiral catalysts for the reaction are those described analogously for asymmetric reductions of ketones, for example described in the references cited below or in the references cited in each of them:

-   Angew. Chem. Int. Ed. 2001 (40) p. 40-73, -   Tetrahedron Lett. 1999 (40) 5043-5046, -   J. Org. Chem. 1996, 61, 4872-4873 -   Angew. Chem. Int. Ed. 2004 (116) 806-843, specifically pages 829-830     and literature cited there, -   Tetrahedron Asymmetry. 2003 (14) 1407-1446, -   Org. Lett 1999 (1) 1119-1121, -   Tetrahedron 2003 (59) 8291-8327.

Suitable catalysts for the reductions are, for example,

-   1. Ruthenium diphosphine 1,2-diamine complexes of the formula (1)     and (2) and analogous complexes of the formulae (1′) or (2′) with     other diamine bridges

-   -   where, in each case,     -   Ar is an aryl radical, preferably phenyl radical, which is         unsubstituted or substituted,     -   D* is a chiral organic group,     -   R^(a), R^(b), R^(c) and R^(d) are each hydrogen or optionally         substituted aliphatic or aromatic groups which may also be         joined to one another in pairs, where the 1,2-diamine bridge is         chiral or achiral in the case of the compound (1) and is chiral         in the case of the compound (2),     -   A* is alkylene having from 1 to 4 carbon atoms, preferably 2         carbon atoms, between the binding sites, where alkylene is         optionally substituted, preferably unsubstituted, or is         substituted by one or more radicals selected from the group         consisting of halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy,         (C₁-C₄)alkylthio and (C₁-C₄)haloalkyl, or cycloalkylene which         has from 3 to 6 carbon atoms and is unsubstituted or substituted         by one or more radicals selected from the group consisting of         halogen, (C₁-C₄)alkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and         (C₁-C₄)haloalkyl, preferably correspondingly optionally         substituted 1,2-cycloalkylene, or a divalent heterocyclic         radical which has from 3 to 6 ring atoms and 1, 2 or 3         heterocyclic ring atoms from the group of O, S and N, where the         ring is unsubstituted or substituted by one or more radicals         selected from the group consisting of halogen, (C₁-C₄)alkyl,         (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and (C₁-C₄)haloalkyl.

The compounds (1) and (2) or (1′) and (2′) may be prepared from ruthenium salts and the diphosphine bridge and diamine bridge compounds before the hydrogenation or in situ.

Examples of diphenylphosphine bridges Ar₂P-D*-PAr₂ for preparing catalysts (1) or (1′) are compounds of the formula (1a), (1b) and (1c):

especially the compounds:

(S)-BINAP: Ar=phenyl[1,1′-binaphthyl-2,2′-bis-(diphenylphosphine)]

(S)-TolBINAP: Ar=4-tolyl[1,1′-binaphthyl-2,2′-bis-(di-p-tolylphosphine)]

(S)-XylBINAP: Ar=3,5-xylyl[1,1′-binaphthyl-2,2′-bis-(di-m-xylylphosphine)] and correspondingly

(R)-BINAP, (R)-TolBINAP and (R)-XylBINAP

Examples of chiral diamine bridges for the preparation of catalysts (1) and (2) or (1′) and (2′) are the following compounds:

(S,S)-DPEN=(1S,2S)-1,2-diamino-1,2-diphenylethane,

(S,S)-1,2-diaminocyclohexane,

(S)-DAIPEN=(2S)-1,2-diamino-1,1-bis-(4-methoxyphenyl)-3-methylbutane,

3,4-O-isopropylidene-(3S,4S)-dihydroxy-(2S,5S)-diaminohexane and correspondingly the enantiomeric compounds

(R,R)-DPEN, (R,R)-1,2-diaminocyclohexane, (R)-DAIPEN and

3,4-O-isopropylidene-(3R,4R)-dihydroxy-(2R,5R)-diaminohexane.

An example of a useful achiral diamine for preparing compounds (1) or (1′) is 1,2-diaminoethane.

-   2. Corresponding to the ruthenium complexes specified under 1, it is     also possible to use similar iridium complexes, for example     [Ir((R)-BINAP)(cod)]BF₄+P[C₆H₄-2-N(CH₃)₂]₂C₆H₅, where “cod” means     the ligand cyclooctadiene. -   3. Corresponding to the ruthenium complexes specified under 1, it is     also possible to use similar iridium complexes, for example     (R,S,R,S)-Me-PennPhos-Rh oxoProNOP—Rh -   4. Metal complexes of the formula (3)

-   -   in which     -   M is a metal(II) ion from the group of Ru, Rh and Ir,     -   X is O or NR*R**,     -   Ar is an aryl radical, preferably phenyl, which is unsubstituted         or substituted, especially alkylphenyl,     -   R^(a), R^(b) and R^(c) are optionally substituted aliphatic or         aromatic groups which may also be joined to one another in         pairs, the bridge being chiral, and     -   R, R*, R** and R*** are each independently a free electron pair,         H, alkyl or acyl,     -   especially corresponding ruthenium(II) 1,2-diamine complexes.

-   5. Rhodium(III) and iridium(III) complexes of the formulae (4)     and (5) which contain chiral ligands and their enantiomeric forms

in which M is an Rh or Ir and R^(a), R^(b) and R^(c) are each organic radicals. Some catalysts from this group are also commercially available (®Cathy catalysts from Avecia), for example rhodium(III) and iridium(III) complexes of the formulae (4a) or (4b) which contain chiral bicyclic ligands and their enantiomeric forms

The asymmetric hydrogenation can generally be carried out by hydrogenating the compound of the formula (II) in a suitable solvent in the presence of a suitable amount of the dissolved catalyst, optionally with addition of bases. The catalyst may optionally also be obtained in situ during the reaction from the components.

The hydrogenation may be effected, for example, as an asymmetric hydrogenation using hydrogen gas as a hydrogen donor or under conditions of asymmetric transfer hydrogenation with other hydrogen donors.

The quantitative ratio of compound (II) to catalyst may be varied within a wide range and is generally in the range from 100 000 mol to 10 mol of compound (II) per mole of the catalyst, preferably from 100 000 mol to 50 mol, in particular from 10 000 mol to 100 mol, of compound (II) per mole of the catalyst.

The suitable temperatures for the inventive reaction may be determined in preliminary experiments. They are generally within a temperature range of from −80° C. up to the boiling point of the mixture, preferably at temperatures of from 0° C. to 100° C., in particular from 15° C. to 60° C., very particularly at room temperature. The reaction is usually carried out at a hydrogen pressure of from 1 to 100 bar, preferably from 1 bar to 10 bar.

Suitable solvents for the catalytic hydrogenation are solvents inert under the reaction conditions, as are typically used in hydrogenation reactions, or mixtures thereof, for example

-   -   alkanols such as methanol, ethanol, n-propanol, isopropanol,         n-butanol, isobutanol, sec-butanol, t-butanol,     -   water,     -   carboxylic esters such as ethyl acetate,     -   carboxylic acids such as glacial acetic acid,     -   aromatic or aliphatic hydrocarbons such as benzene, toluene,         xylene and paraffins, preferably toluene, xylene or mesitylene         or else mixtures such as ®Solvesso (mineral oil mixture with         aromatic fractions),     -   halogenated aliphatic or aromatic hydrocarbons, for example         chlorinated alkanes and alkenes, chlorobenzene,         o-dichlorobenzene,     -   nitriles such as acetonitrile,     -   ethers such as diethyl ether or cyclic ethers such as dioxane or         tetrahydrofuran,     -   amides such as dimethylformamide, sulfones such as sulfolane,         and mixtures of the solvents mentioned.

As a variant of the hydrogenation, an asymmetric transfer hydrogenation may be carried out with a hydrogen donor in the presence of the above-described catalysts. Suitable hydrogen donors are compounds which can themselves be oxidized under the conditions. Suitable hydrogen donors are, for example, formic acid and its salts, as are also used for the performance of the Leukart-Wallach reaction (see, for example, Houben-Weyl 11/1, 648-664 and Synthesis 1988, 92 and literature cited there). A suitable hydrogen donor is thus formic acid which can be used optionally in combination with a base, for example a tertiary amine base. Bases are, for example, ammonia or primary, secondary and tertiary amines, for example those with alkyl, aralkyl and/or aryl radicals, preferably corresponding amines with (C₁-C₄)alkyl radicals. Suitable salts are corresponding (substituted) ammonium formates. Further hydrogen donors are isopropanol or cyclohexadiene (cf. Adv. Synth. Catal. 2003, Vol. 345, pages 67-77, Tetrahedron: Asymmetry 10 (1999) 2045-2061, Eur. J. Inorg. Chem. 2002, 2239-2251), also in each case in combination with the catalysts mentioned specifically in the references.

Preference is given to the use of catalysts of the abovementioned formulae (3), (4) and (5) in combination with formic acid and tertiary amines such as triethylamine.

Suitable mixing ratios of formic acid:amine are from 10:1 to 1:10 based on the weight. The donor system may be used directly as a solvent or be used in a mixture with other solvents as cosolvents.

Suitable solvents for the catalytic transfer hydrogenation are solvents inert under the reaction conditions or mixtures thereof, for example

-   -   alkanols such as methanol, ethanol, n-propanol, isopropanol,         n-butanol, isobutanol, sec-butanol, t-butanol,     -   water,     -   carboxylic esters such as ethyl acetate,     -   carboxylic acids such as glacial acetic acid,     -   aromatic or aliphatic hydrocarbons such as benzene, toluene,         xylene and paraffins, preferably toluene, xylene or mesitylene         or else mixtures such as ®Solvesso (mineral oil mixture with         aromatic fractions),     -   halogenated aliphatic or aromatic hydrocarbons, for example         chlorinated alkanes and alkenes, chlorobenzene,         o-dichlorobenzene,     -   nitriles such as acetonitrile,     -   ethers such as diethyl ether or cyclic ethers such as dioxane or         tetrahydrofuran,     -   amides such as dimethylformamide, sulfones such as sulfolane,         and mixtures of the solvents mentioned.

The catalytic hydrogenation and the catalytic transfer hydrogenation may be carried out analogously to the customary conditions, as described in the literature mentioned for the reduction of ketones to optically active alcohols.

The performance of the reaction with regard to amount of catalyst and reaction time should be optimized in preliminary experiments in order to achieve a high conversion rate, chemical yield and enantiomeric excess.

Surprisingly, it is possible in the hydrogenations to achieve good enantioselectivity of the amine (I) not only with regard to the chiral center at which the amino group is bonded but also with regard to the adjacent chiral center.

The starting materials of the formula (II) are known or can be prepared analogously to known processes. A simple possibility is the preparation via the corresponding ketone. Cyclic ketones are in many cases commercially available or can be prepared by a large number of reactions known to those skilled in the art from other compounds such as alcohols, halogen compounds, or from esters or carboxylic acids by ring-closure reactions. Bicyclic ketones are, for example, also described in WO 97/031904 and WO 2004/069814.

A particular means of preparing the optically active amines (I) and their salts also consists in carrying out a two-stage process with in situ preparation of the imine from a corresponding ketone and direct reduction in the presence of the catalyst. The imine is formed by reaction of the ketone with a suitable amount of a primary amine R⁰—NH₂ where R⁰ is as defined in formula (I) and is reduced to the amine without intermediate isolation. The in situ process can be carried out, for example, with an amount of from 0.1 mol up to a several-fold excess of primary amine per mole of ketone, preferably from 1 to 10 mol, in particular from 1 to 5 mol, more preferably from 1 to 2 mol, of primary amine per mole of ketone. The two-stage reaction can generally be controlled by adding the optically active catalyst. The temperature conditions depend substantially upon the suitable temperature for the catalytic reaction.

The resulting compounds of the formula (I) are suitable as optically active synthons for preparing optically active active ingredients. A particularly frequent use of the compounds (I) and their salts is the preparation of the corresponding free amines (I′), the difference of the formula (I′) from the formula (I) consisting in the replacement of the R⁰ radical by hydrogen.

The free optically active cis-amines of the formula (I′) and their salts therefore likewise form part of the subject matter of the invention. They can be prepared from suitable compounds of the formula (I) by standard reactions, for example by elimination of protecting groups R⁰ for which an elimination reaction, preferably a gentle elimination reaction, is known. Examples of such eliminable groups are the groups i)-xv) mentioned above. The preparation of these groups and their common and preferred elimination methods are described, for example, in the handbook “Protective Groups in Organic Synthesis, 3^(rd) ed., T. W. Greene and P. G. M. Wuts; 1999, John Wiley & Sons, Inc. (see in particular pages 575 to 585) and literature cited there.

The experiments are illustrated in detail by the examples which follow without any intention that the invention be restricted to these embodiments. Amounts are based on weight unless stated otherwise.

ABBREVIATIONS IN THE EXAMPLES

-   Me=methyl -   Et=ethyl -   n- or i-Pr or t-butyl=n-propyl or isopropyl or t-butyl -   Ph=phenyl -   Ts=p-tosyl=p-tolylsulfonyl -   Allyl=CH₂—CH═CH₂ -   Bzl=benzyl ═CH₂Ph -   p-MeO-Bzl=para-methoxybenzyl=(p-methoxyphenyl)methyl

EXAMPLE A1 cis-(S,S)-Benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine A1a) Preparation of the catalyst Ru(p-cymene)-(S,S)-TsDPEN

Bis(p-cymeneruthenium dichloride) is initially charged in an organic solvent and reacted at room temperature with (S,S)-TsDPEN [(S,S)-N-tosyl-1,2-diamino-1,2-diphenylethane]. Concentration and removal of the solvent under high vacuum affords Ru(p-cymene)(S,S)-TsDPEN of the formula:

Correspondingly, the compound Ru(p-cymene)(R,R)-TsDPEN is obtained using (R,R)-TsDPEN.

A1b) (1S,2S)-N-Benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine

3 mg (4.7 μmol) of the catalyst from example Ala are dissolved in 1 ml of a mixture of formic acid and triethylamine (5:2 v/v) and stirred for 20 min. A solution of 350 mg (1.141 mmol) of racemic N-benzyl-(2-methyl-3,4-dihydro-2H-naphth-1-ylidene)amine in 1.7 ml of dichloromethane is then added and the mixture is stirred at room temperature for 5 days. After removal of the solvent, the dissolution in 5 ml of methanol, treatment with approx. 200 mg of potassium hydroxide and admixing with 10 ml of water at room temperature, extraction is effected three times with in each case 15 ml of dichloromethane and the organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (20:1 hexane/ethyl acetate), 229 mg (65% yield) of (1S,2S)-N-benzyl-(2-methyl-1,2,3,4-tetrahydronaphth-1-yl)amine are obtained as a light yellow oil.

[α]²¹ _(D)=−31.1° (c 0.8, CHCl₃); ¹H NMR (400 MHz, C₆D₆) δ=6.98-7.22 (m, 9H), 3.75 (d, 1H, J=14.0 Hz), 3.71 (d, 1H, J=14.0 Hz), 3.47 (d, 1H, J=3.6 Hz), 2.68 (dt, 1H, J=17.2, 5.6 Hz), 2.55 (dt, 1H, J=16.8, 8.0 Hz), 1.84 (m, 4H), 1.63 (m, 1H), 1.48 (m, 1H), 0.95 (d, 3H, J=6.5 Hz), ¹³C NMR (100 MHz, C₆D₆) δ=141.8, 140.2, 136.5, 129.5, 129.2, 128.7, 128.6, 127.2, 127.0, 125.8, 259.3, 52.6, 32.5, 28.0, 26.5, 16.5. The enantiomeric excess (ee %) was determined by chromatography (ee=98%); HPLC on Chiralpak AD (Daicel), 96:4 n-hexane:isopropanol, 30° C., flow rate: 0.5 ml/min; RT: 7.07 min.

EXAMPLE A2 (1R,2S)-N-Allyl-(2-methylcyclohexyl)amine

A solution of 22.5 mg (35 μmol) of the catalyst from example Ala in 3.2 ml of a mixture of formic acid and triethylamine (5:2 v/v) is added dropwise to a mixture of 676 mg (6 mmol) of 2-methylcyclohexanone, 2.74 g (48 mmol of allylamine and 100 mg of magnesium sulfate, and stirred. After 7 days at room temperature, the reaction mixture is diluted with 20 ml of water and extracted three times with 15 ml of dichloromethane. The organic phase is dried over sodium sulfate. After removal of the solvent and column chromatography (silica gel, 10:1 dichloromethane/methanol), 708 mg (77% yield) of (1R,2S)-N-allyl-(2-methylcyclohexyl)amine are obtained.

[α]²¹ _(D)=+8.2° (c 0.7, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ=5.88 (m, 1H), 5.14 (dd, 1H, J=1.6, 16.2 Hz), 5.03 (m, 1H), 3.19 (m, 1H), 2.58 (m, 1H), 1.90 (m, 1H), 1.7-1.2 (m, 9H), 0.86 (d, 1H, J=7.0 Hz),

¹³C NMR (75 MHz) δ=137.8, 115.8, 58.8, 49.9, 31.4, 28.4, 24.1, 22.2, 19.6, 13.8.

The enantiomeric excess (ee %) was determined by chromatography (ee=95.9%); HPLC on Chiralpak OJ (Daicel), 99.5:0.5 n-hexane:isopropanol, 30° C., flow rate: 0.5 ml/min; RT: 17.16 min.

EXAMPLE A3 (1R,2R)-N-Benzyl-(2-phenylcyclohexyl)amine

16.6 mg of IrCl[(S,S)-TsDPEN]Cp* and a solution of racemic 1-benzyl-N-[2-phenylcyclohexylidene]amine in 10 ml of dry dichloromethane are added to 3.2 ml of a mixture of formic acid and triethylamine (5:2 v/v). After stirring at room temperature for 24 h, the mixture is diluted with 0.5 M aq. Na₂CO₃ until pH 10 is attained and then extracted with dichloromethane (2×30 ml). The organic phase is subsequently dried over magnesium sulfate and concentrated under reduced pressure, and the residue is purified by column chromatography (silica gel, 1:12 ethyl acetate/hexane). (1R,2R)-N-Benzyl-(2-phenylcyclohexyl)amine is obtained in 60% yield. [α]²² _(D)=+33.4° (c 0.7, CHCl₃); ¹H NMR (300 MHz, CDCl₃) δ=6.9-7.4 (m, 10H), 3.68 (d, J=13.8 Hz, 1H), 3.0 (m, 1H), 2.85 (dt, J=13.3, 3.2 Hz), 1H), 1.1-2.2 (m, 8H);

¹³C NMR (75 MHz) δ=143.9, 140.3, 127.7, 127.5, 127.1, 125.9, 125.5, 56.1, 50.7, 46.5, 29.2, 25.9, 24.1, 19.1. The diastereomeric excess (de) was determined by means of ¹H-NMR (de>98%). The enantiomeric excess was determined after debenzylation and subsequent acetylation of the released amino function (ee=50%).

According to examples A1, A2 and A3 and the variants mentioned in the description, the example compounds mentioned in the following tables 1 and 2 are also obtained.

Comments on Tables 1 and 2:

Methods for determining the retention time by HPLC on chiral phase. All measurements with n-hexane/isopropanol as eluent at 30° C. References reported as follows: R_(t) (min), eluent and flow rate (v_(nHex)/v_(iProH)−ml/min)

⁽¹⁾ Chiralpak AD (Daicel)

⁽²⁾ Chiralpak OJ (Daicel)

⁽³⁾ Chiralpak OB (Daicel)

⁽⁴⁾ characterized as the N-benzoyl derivative

Some data on the compounds are reported at the end of each table.

TABLE 1 Compounds of the formula (Ia-A) and (Ia-B) (Ia-A)

(Ia-B)

The numbers in the first column of the table relate to the compounds of the formula (Ia-A) with the substituent definitions in the columns under A, R⁰ and R¹. Correspondingly, the numbers in the second column relate to the compounds of the formula (Ia-B) with the substituent definitions in the columns under A, R⁰ and R¹. Comp. (Ia-A) Comp. (Ia-B) No. No. A R⁰ R¹ aA1 aB1 CH₂ Me Me aA2 aB2 CH₂CH₂ Me Me aA3 aB3 CH₂CH₂CH₂ Me Me aA4 aB4 CH₂CH₂CH₂CH₂ Me Me aA5 aB5 CH₂CH₂CH₂CH₂CH₂ Me Me aA6 aB6 CH₂O Me Me aA7 aB7 CH₂OCH₂ Me Me aA8 aB8 CH₂ Me Et aA9 aB9 CH₂ Me n-Pr aA10 aB10 CH₂CH₂ Me Et aA11 aB11 CH₂CH₂ Me n-Pr aA12 aB12 CH₂CH₂CH₂ Me Et aA13 aB13 CH₂CH₂CH₂ Me n-Pr aA14 aB14 CH₂CH₂CH₂CH₂ Me Et aA15 aB15 CH₂CH₂CH₂CH₂ Me n-Pr aA16 aB16 CH₂CH₂CH₂CH₂CH₂ Me Et aA17 aB17 CH₂CH₂CH₂CH₂CH₂ Me n-Pr aA18 aB18 CH₂O Me Et aA19 aB19 CH₂O Me n-Pr aA20 aB20 CH₂OCH₂ Me Et aA21 aB21 CH₂OCH₂ Me n-Pr aA22 aB22 CH₂ Et Me aA23 aB23 CH₂CH₂ Et Me aA24 aB24 CH₂CH₂CH₂ Et Me aA25 aB25 CH₂CH₂CH₂CH₂ Et Me aA26 aB26 CH₂CH₂CH₂CH₂CH₂ Et Me aA27 aB27 CH₂O Et Me aA28 aB28 CH₂OCH₂ Et Me aA29 aB29 CH₂ Et Et aA30 aB30 CH₂ Et n-Pr aA31 aB31 CH₂CH₂ Et Et aA32 aB32 CH₂CH₂ Et n-Pr aA33 aB33 CH₂CH₂CH₂ Et Et aA34 aB34 CH₂CH₂CH₂ Et n-Pr aA35 aB35 CH₂CH₂CH₂CH₂ Et Et aA36 aB36 CH₂CH₂CH₂CH₂ Et n-Pr aA37 aB37 CH₂CH₂CH₂CH₂CH₂ Et Et aA38 aB38 CH₂CH₂CH₂CH₂CH₂ Et n-Pr aA39 aB39 CH₂O Et Et aA40 aB40 CH₂O Et n-Pr aA41 aB41 CH₂OCH₂ Et Et aA42 aB42 CH₂OCH₂ Et n-Pr aA43 aB43 CH₂ Allyl Me aA44 aB44 CH₂CH₂ Allyl Me aA45 aB45 CH₂CH₂CH₂ Allyl Me aA46 aB46 CH₂CH₂CH₂CH₂ Allyl Me aA47 aB47 CH₂CH₂CH₂CH₂CH₂ Allyl Me aA48 aB48 CH₂O Allyl Me aA49 aB49 CH₂OCH₂ Allyl Me aA50 aB50 CH₂ Allyl Et aA51 aB51 CH₂ Allyl n-Pr aA52 aB52 CH₂CH₂ Allyl Et aA53 aB53 CH₂CH₂ Allyl n-Pr aA54 aB54 CH₂CH₂CH₂ Allyl Et aA55 aB55 CH₂CH₂CH₂ Allyl n-Pr aA56 aB56 CH₂CH₂CH₂CH₂ Allyl Et aA57 aB57 CH₂CH₂CH₂CH₂ Allyl n-Pr aA58 aB58 CH₂CH₂CH₂CH₂CH₂ Allyl Et aA59 aB59 CH₂CH₂CH₂CH₂CH₂ Allyl n-Pr aA60 aB60 CH₂O Allyl Et aA61 aB61 CH₂O Allyl n-Pr aA62 aB62 CH₂OCH₂ Allyl Et aA63 aB63 CH₂OCH₂ Allyl n-Pr aA64 aB64 CH₂ Bzl Me aA65 aB65 CH₂CH₂ Bzl Me aA66 aB66 CH₂CH₂CH₂ Bzl Me aA67 aB67 CH₂CH₂CH₂CH₂ Bzl Me aA68 aB68 CH₂CH₂CH₂CH₂CH₂ Bzl Me aA69 aB69 CH₂O Bzl Me aA70 aB70 CH₂OCH₂ Bzl Me aA71 aB71 CH₂ Bzl Et aA72 aB72 CH₂ Bzl n-Pr aA73 aB73 CH₂ Bzl Ph aA74 aB74 CH₂CH₂ Bzl Et aA75 aB75 CH₂CH₂ Bzl n-Pr aA76 aB76 CH₂CH₂ Bzl Ph aA77 aB77 CH₂CH₂CH₂ Bzl Et aA78 aB78 CH₂CH₂CH₂ Bzl n-Pr aA79 aB79 CH₂CH₂CH₂ Bzl Ph aA80 aB80 CH₂CH₂CH₂CH₂ Bzl Et aA81 aB81 CH₂CH₂CH₂CH₂ Bzl n-Pr aA82 aB82 CH₂CH₂CH₂CH₂ Bzl Ph aA83 aB83 CH₂CH₂CH₂CH₂CH₂ Bzl Et aA84 aB84 CH₂CH₂CH₂CH₂CH₂ Bzl n-Pr aA85 aB85 CH₂CH₂CH₂CH₂CH₂ Bzl Ph aA86 aB86 CH₂O Bzl Et aA87 aB87 CH₂O Bzl n-Pr aA88 aB88 CH₂O Bzl Ph aA89 aB89 CH₂OCH₂ Bzl Et aA90 aB90 CH₂OCH₂ Bzl n-Pr aA91 aB91 CH₂OCH₂ Bzl Ph Physical data on compounds from table 1: Compound No.: aB46: Ref(^(2,4)) R_(t) = 17.2, n-hexane/isopropanol = 99.5:0.5 (v/v), flow rate = 0.5 ml/mm

TABLE 2 Compounds of the formula (Ib-A) and (Ib-B) (Ib-A)

(Ib-B)

The numbers in the first column of the table relate to the compounds of the formula (Ib-A) with the substituent definitions in the columns under A, R⁰ to R⁵. Correspondingly, the numbers in the second column relate to the compounds of the formula (Ib-B) with the substituent definitions in the columns under A and R⁰ to R⁵. Ib-A Ib-B A¹ R⁰ R¹ R² R³ R⁴ R⁵ bA1 bB1 — Me Me H H H H bA2 bB2 — Me Me Me H H H bA3 bB3 — Me Me H Me H H bA4 bB4 — Me Me H H Me H bA5 bB5 — Me Me H H H Me bA6 bB6 — Me Me Cl H H H bA7 bB7 — Me Me H Cl H H bA8 bB8 — Me Me H H Cl H bA9 bB9 — Me Me H H H Cl bA10 bB10 — Me Me Et H H H bA11 bB11 — Me Me H Et H H bA12 bB12 — Me Me H H Et H bA13 bB13 — Me Me H H H Et bA14 bB14 — Me Me OMe H H H bA15 bB15 — Me Me H OMe H H bA16 bB16 — Me Me H H OMe H bA17 bB17 — Me Me H H H OMe bA18 bB18 — Me Me F H H H bA19 bB19 — Me Me H F H H bA20 bB20 — Me Me H H F H bA21 bB21 — Me Me H H H F bA22 bB22 — Et Me H H H H bA23 bB23 — Et Me Me H H H bA24 bB24 — Et Me H Me H H bA25 bB25 — Et Me H H Me H bA26 bB26 — Et Me H H H Me bA27 bB27 — Et Me Cl H H H bA28 bB28 — Et Me H Cl H H bA29 bB29 — Et Me H H Cl H bA30 bB30 — Et Me H H H Cl bA31 bB31 — Et Me Et H H H bA32 bB32 — Et Me H Et H H bA33 bB33 — Et Me H H Et H bA34 bB34 — Et Me H H H Et bA35 bB35 — Et Me OMe H H H bA36 bB36 — Et Me H OMe H H bA37 bB37 — Et Me H H OMe H bA38 bB38 — Et Me H H H OMe bA39 bB39 — Et Me F H H H bA40 bB40 — Et Me H F H H bA41 bB41 — Et Me H H F H bA42 bB42 — Et Me H H H F bA43 bB43 — Allyl Me H H H H bA44 bB44 — Allyl Me Me H H H bA45 bB45 — Allyl Me H Me H H bA46 bB46 — Allyl Me H H Me H bA47 bB47 — Allyl Me H H H Me bA48 bB48 — Allyl Me Cl H H H bA49 bB49 — Allyl Me H Cl H H bA50 bB50 — Allyl Me H H Cl H bA51 bB51 — Allyl Me H H H Cl bA52 bB52 — Allyl Me Et H H H bA53 bB53 — Allyl Me H Et H H bA54 bB54 — Allyl Me H H Et H bA55 bB55 — Allyl Me H H H Et bA56 bB56 — Allyl Me OMe H H H bA57 bB57 — Allyl Me H OMe H H bA58 bB58 — Allyl Me H H OMe H bA59 bB59 — Allyl Me H H H OMe bA60 bB60 — Allyl Me F H H H bA61 bB61 — Allyl Me H F H H bA62 bB62 — Allyl Me H H F H bA63 bB63 — Allyl Me H H H F bA64 bB64 — Bzl Me H H H H bA65 bB65 — Bzl Me Me H H H bA66 bB66 — Bzl Me H Me H H bA67 bB67 — Bzl Me H H Me H bA68 bB68 — Bzl Me H H H Me bA69 bB69 — Bzl Me Cl H H H bA70 bB70 — Bzl Me H Cl H H bA71 bB71 — Bzl Me H H Cl H bA72 bB72 — Bzl Me H H H Cl bA73 bB73 — Bzl Me Et H H H bA74 bB74 — Bzl Me H Et H H bA75 bB75 — Bzl Me H H Et H bA76 bB76 — Bzl Me H H H Et bA77 bB77 — Bzl Me OMe H H H bA78 bB78 — Bzl Me H OMe H H bA79 bB79 — Bzl Me H H OMe H bA80 bB80 — Bzl Me H H H OMe bA81 bB81 — Bzl Me F H H H bA82 bB82 — Bzl Me H F H H bA83 bB83 — Bzl Me H H F H bA84 bB84 — Bzl Me H H H F bA85 bB85 — p-MeO-Bzl Me H H H H bA86 bB86 — p-MeO-Bzl Me Me H H H bA87 bB87 — p-MeO-Bzl Me H Me H H bA88 bB88 — p-MeO-Bzl Me H H Me H bA89 bB89 — p-MeO-Bzl Me H H H Me bA90 bB90 — p-MeO-Bzl Me Cl H H H bA91 bB91 — p-MeO-Bzl Me H Cl H H bA92 bB92 — p-MeO-Bzl Me H H Cl H bA93 bB93 — p-MeO-Bzl Me H H H Cl bA94 bB94 — p-MeO-Bzl Me Et H H H bA95 bB95 — p-MeO-Bzl Me H Et H H bA96 bB96 — p-MeO-Bzl Me H H Et H bA97 bB97 — p-MeO-Bzl Me H H H Et bA98 bB98 — p-MeO-Bzl Me OMe H H H bA99 bB99 — p-MeO-Bzl Me H OMe H H bA100 bB100 — p-MeO-Bzl Me H H OMe H bA101 bB101 — p-MeO-Bzl Me H H H OMe bA102 bB102 — p-MeO-Bzl Me F H H H bA103 bB103 — p-MeO-Bzl Me H F H H bA104 bB104 — p-MeO-Bzl Me H H F H bA105 bB105 — p-MeO-Bzl Me H H H F bA106 bB106 — i-Pr Me Me H H F bA107 bB107 — i-Pr Me H Me H H bA108 bB108 — i-Pr Me H H Me H bA109 bB109 — i-Pr Me H H H Me bA110 bB110 — i-Pr Me Cl H H H bA111 bB111 — i-Pr Me H Cl H H bA112 bB112 — i-Pr Me H H Cl H bA113 bB113 — i-Pr Me H H H Cl bA114 bB114 — i-Pr Me Et H H H bA115 bB115 — i-Pr Me H Et H H bA116 bB116 — i-Pr Me H H Et H bA117 bB117 — i-Pr Me H H H Et bA118 bB118 — i-Pr Me OMe H H H bA119 bB119 — i-Pr Me H OMe H H bA120 bB120 — i-Pr Me H H OMe H bA121 bB121 — i-Pr Me H H H OMe bA122 bB122 — i-Pr Me F H H H bA123 bB123 — i-Pr Me H F H H bA124 bB124 — i-Pr Me H H F H bA125 bB125 — i-Pr Me H H H F bA126 bB126 — t-Bu Me H H H H bA127 bB127 — t-Bu Me Me H H H bA128 bB128 — t-Bu Me Me Me H H bA129 bB129 — t-Bu Me H H Me H bA130 bB130 — t-Bu Me H H H Me bA131 bB131 — t-Bu Me Cl H H H bA132 bB132 — t-Bu Me H Cl H H bA133 bB133 — t-Bu Me H H Cl H bA134 bB134 — t-Bu Me H H H Cl bA135 bB135 — t-Bu Me H H H H bA136 bB136 — t-Bu Me Et H H H bA137 bB137 — t-Bu Me H Et H H bA138 bB138 — t-Bu Me H H Et H bA139 bB139 — t-Bu Me H H H Et bA140 bB140 — t-Bu Me OMe H H H bA141 bB141 — t-Bu Me H OMe H H bA142 bB142 — t-Bu Me H H OMe H bA143 bB143 — t-Bu Me H H H OMe bA144 bB144 — t-Bu Me F H H H bA145 bB145 — t-Bu Me H F H H bA146 bB146 — t-Bu Me H H F H bA147 bB147 — t-Bu Me H H H F bA148 bB148 — Ph Me H H H H bA149 bB149 — Ph Me Me H H H bA150 bB150 — Ph Me Me Me H H bA151 bB151 — Ph Me H H Me H bA152 bB152 — Ph Me H H H Me bA153 bB153 — Ph Me Cl H H H bA154 bB154 — Ph Me H Cl H H bA155 bB155 — Ph Me H H Cl H bA156 bB156 — Ph Me H H H Cl bA157 bB157 — Ph Me H H H H bA158 bB158 — Ph Me Et H H H bA159 bB159 — Ph Me H Et H H bA160 bB160 — Ph Me H H Et H bA161 bB161 — Ph Me H H H Et bA162 bB162 — Ph Me OMe H H H bA163 bB163 — Ph Me H OMe H H bA164 bB164 — Ph Me H H OMe H bA165 bB165 — Ph Me H H H OMe bA166 bB166 — Ph Me F H H H bA167 bB167 — Ph Me H F H H bA168 bB168 — Ph Me H H F H bA169 bB169 — Ph Me H H H F bA170 bB170 CH₂ Me Me H H H H bA171 bB171 CH₂ Me Me Me H H H bA172 bB172 CH₂ Me Me H Me H H bA173 bB173 CH₂ Me Me H H Me H bA174 bB174 CH₂ Me Me H H H Me bA175 bB175 CH₂ Me Me Cl H H H bA176 bB176 CH₂ Me Me H Cl H H bA177 bB177 CH₂ Me Me H H Cl H bA178 bB178 CH₂ Me Me H H H Cl bA179 bB179 CH₂ Me Me Et H H H bA180 bB180 CH₂ Me Me H Et H H bA181 bB181 CH₂ Me Me H H Et H bA182 bB182 CH₂ Me Me H H H Et bA183 bB183 CH₂ Me Me OMe H H H bA184 bB184 CH₂ Me Me H OMe H H bA185 bB185 CH₂ Me Me H H OMe H bA186 bB186 CH₂ Me Me H H H OMe bA187 bB187 CH₂ Me Me F H H H bA188 bB188 CH₂ Me Me H F H H bA189 bB189 CH₂ Me Me H H F H bA190 bB190 CH₂ Me Me H H H F bA191 bB191 CH₂ Et Me H H H H bA192 bB192 CH₂ Et Me Me H H H bA193 bB193 CH₂ Et Me H Me H H bA194 bB194 CH₂ Et Me H H Me H bA195 bB195 CH₂ Et Me H H H Me bA196 bB196 CH₂ Et Me Cl H H H bA197 bB197 CH₂ Et Me H Cl H H bA198 bB198 CH₂ Et Me H H Cl H bA199 bB199 CH₂ Et Me H H H Cl bA200 bB200 CH₂ Et Me Et H H H bA201 bB201 CH₂ Et Me H Et H H bA202 bB202 CH₂ Et Me H H Et H bA203 bB203 CH₂ Et Me H H H Et bA204 bB204 CH₂ Et Me OMe H H H bA205 bB205 CH₂ Et Me H OMe H H bA206 bB206 CH₂ Et Me H H OMe H bA207 bB207 CH₂ Et Me H H H OMe bA208 bB208 CH₂ Et Me F H H H bA209 bB209 CH₂ Et Me H F H H bA210 bB210 CH₂ Et Me H H F H bA211 bB211 CH₂ Et Me H H H F bA212 bB212 CH₂ Allyl Me H H H H bA213 bB213 CH₂ Allyl Me Me H H H bA214 bB214 CH₂ Allyl Me H Me H H bA215 bB215 CH₂ Allyl Me H H Me H bA216 bB216 CH₂ Allyl Me H H H Me bA217 bB217 CH₂ Allyl Allyl Me H H H bA218 bB218 CH₂ Allyl Allyl H Me H H bA219 bB219 CH₂ Allyl Allyl H H Me H bA220 bB220 CH₂ Allyl Allyl H H H Me bA221 bB221 CH₂ Allyl Me Cl H H H bA222 bB222 CH₂ Allyl Me H Cl H H bA223 bB223 CH₂ Allyl Me H H Cl H bA224 bB224 CH₂ Allyl Me H H H Cl bA225 bB225 CH₂ Allyl Me Et H H H bA226 bB226 CH₂ Allyl Me H Et H H bA227 bB227 CH₂ Allyl Me H H Et H bA228 bB228 CH₂ Allyl Me H H H Et bA229 bB229 CH₂ Allyl Me OMe H H H bA230 bB230 CH₂ Allyl Me H OMe H H bA231 bB231 CH₂ Allyl Me H H OMe H bA232 bB232 CH₂ Allyl Me H H H OMe bA233 bB233 CH₂ Allyl Me F H H H bA234 bB234 CH₂ Allyl Me H F H H bA235 bB235 CH₂ Allyl Me H H F H bA236 bB236 CH₂ Allyl Me H H H F bA237 bB237 CH₂ Bzl Me H H H H bA238 bB238 CH₂ Bzl Me Me H H H bA239 bB239 CH₂ Bzl Me H Me H H bA240 bB240 CH₂ Bzl Me H H Me H bA241 bB241 CH₂ Bzl Me H H H Me bA242 bB242 CH₂ Bzl Me Cl H H H bA243 bB243 CH₂ Bzl Me H Cl H H bA244 bB244 CH₂ Bzl Me H H Cl H bA245 bB245 CH₂ Bzl Me H H H Cl bA246 bB246 CH₂ Bzl Me Et H H H bA247 bB247 CH₂ Bzl Me H Et H H bA248 bB248 CH₂ Bzl Me H H Et H bA249 bB249 CH₂ Bzl Me H H H Et bA250 bB250 CH₂ Bzl Me OMe H H H bA251 bB251 CH₂ Bzl Me H OMe H H bA252 bB252 CH₂ Bzl Me H H OMe H bA253 bB253 CH₂ Bzl Me H H H OMe bA254 bB254 CH₂ Bzl Me F H H H bA255 bB255 CH₂ Bzl Me H F H H bA256 bB256 CH₂ Bzl Me H H F H bA257 bB257 CH₂ Bzl Me H H H F bA258 bB258 CH₂ p-MeO-Bzl Me H H H H bA259 bB259 CH₂ p-MeO-Bzl Me Me H H H bA260 bB260 CH₂ p-MeO-Bzl Me H Me H H bA261 bB261 CH₂ p-MeO-Bzl Me H H Me H bA262 bB262 CH₂ p-MeO-Bzl Me H H H Me bA263 bB263 CH₂ p-MeO-Bzl Me Cl H H H bA264 bB264 CH₂ p-MeO-Bzl Me H Cl H H bA265 bB265 CH₂ p-MeO-Bzl Me H H Cl H bA266 bB266 CH₂ p-MeO-Bzl Me H H H Cl bA267 bB267 CH₂ p-MeO-Bzl Me Et H H H bA268 bB268 CH₂ p-MeO-Bzl Me H Et H H bA269 bB269 CH₂ p-MeO-Bzl Me H H Et H bA270 bB270 CH₂ p-MeO-Bzl Me H H H Et bA271 bB271 CH₂ p-MeO-Bzl Me OMe H H H bA272 bB272 CH₂ p-MeO-Bzl Me H OMe H H bA273 bB273 CH₂ p-MeO-Bzl Me H H OMe H bA274 bB274 CH₂ p-MeO-Bzl Me H H H OMe bA275 bB275 CH₂ p-MeO-Bzl Me F H H H bA276 bB276 CH₂ p-MeO-Bzl Me H F H H bA277 bB277 CH₂ p-MeO-Bzl Me H H F H bA278 bB278 CH₂ p-MeO-Bzl Me H H H F bA279 bB279 CH₂ i-Pr Me Me H H F bA280 bB280 CH₂ i-Pr Me H Me H H bA281 bB281 CH₂ i-Pr Me H H Me H bA282 bB282 CH₂ i-Pr Me H H H Me bA283 bB283 CH₂ i-Pr Me Cl H H H bA284 bB284 CH₂ i-Pr Me H Cl H H bA285 bB285 CH₂ i-Pr Me H H Cl H bA286 bB286 CH₂ i-Pr Me H H H Cl bA287 bB287 CH₂ i-Pr Me Et H H H bA288 bB288 CH₂ i-Pr Me H Et H H bA289 bB289 CH₂ i-Pr Me H H Et H bA290 bB290 CH₂ i-Pr Me H H H Et bA291 bB291 CH₂ i-Pr Me OMe H H H bA292 bB292 CH₂ i-Pr Me H OMe H H bA293 bB293 CH₂ i-Pr Me H H OMe H bA294 bB294 CH₂ i-Pr Me H H H OMe bA295 bB295 CH₂ i-Pr Me F H H H bA296 bB296 CH₂ i-Pr Me H F H H bA297 bB297 CH₂ i-Pr Me H H F H bA298 bB298 CH₂ i-Pr Me H H H F bA299 bB299 CH₂ t-Bu Me H H H H bA300 bB300 CH₂ t-Bu Me Me H H H bA301 bB301 CH₂ t-Bu Me M Me H H bA302 bB302 CH₂ t-Bu Me H H Me H bA303 bB303 CH₂ t-Bu Me H H H Me bA304 bB304 CH₂ t-Bu Me Cl H H H bA305 bB305 CH₂ t-Bu Me H Cl H H bA306 bB306 CH₂ t-Bu Me H H Cl H bA307 bB307 CH₂ t-Bu Me H H H Cl bA308 bB308 CH₂ t-Bu Me H H H H bA309 bB309 CH₂ t-Bu Me Et H H H bA310 bB310 CH₂ t-Bu Me H Et H H bA311 bB311 CH₂ t-Bu Me H H Et H bA312 bB312 CH₂ t-Bu Me H H H Et bA313 bB313 CH₂ t-Bu Me OMe H H H bA314 bB314 CH₂ t-Bu Me H OMe H H bA315 bB315 CH₂ t-Bu Me H H OMe H bA316 bB316 CH₂ t-Bu Me H H H OMe bA317 bB317 CH₂ t-Bu Me F H H H bA318 bB318 CH₂ t-Bu Me H F H H bA319 bB319 CH₂ t-Bu Me H H F H bA320 bB320 CH₂ t-Bu Me H H H F bA321 bB321 CH₂ Ph Me H H H H bA322 bB322 CH₂ Ph Me Me H H H bA323 bB323 CH₂ Ph Me Me Me H H bA324 bB324 CH₂ Ph Me H H Me H bA325 bB325 CH₂ Ph Me H H H Me bA326 bB326 CH₂ Ph Me Cl H H H bA327 bB327 CH₂ Ph Me H Cl H H bA328 bB328 CH₂ Ph Me H H Cl H bA329 bB329 CH₂ Ph Me H H H Cl bA330 bB330 CH₂ Ph Me H H H H bA331 bB331 CH₂ Ph Me Et H H H bA332 bB332 CH₂ Ph Me H Et H H bA333 bB333 CH₂ Ph Me H H Et H bA334 bB334 CH₂ Ph Me H H H Et bA335 bB335 CH₂ Ph Me OMe H H H bA336 bB336 CH₂ Ph Me H OMe H H bA337 bB337 CH₂ Ph Me H H OMe H bA338 bB338 CH₂ Ph Me H H H OMe bA339 bB339 CH₂ Ph Me F H H H bA340 bB340 CH₂ Ph Me H F H H bA341 bB341 CH₂ Ph Me H H F H bA342 bB342 CH₂ Ph Me H H H F bA343 bB343 CH₂CH₂ Me Me H H H H bA344 bB344 CH₂CH₂ Me Me Me H H H bA345 bB345 CH₂CH₂ Me Me H Me H H bA346 bB346 CH₂CH₂ Me Me H H Me H bA347 bB347 CH₂CH₂ Me Me H H H Me bA348 bB348 CH₂CH₂ Me Me Cl H H H bA349 bB349 CH₂CH₂ Me Me H Cl H H bA350 bB350 CH₂CH₂ Me Me H H Cl H bA351 bB351 CH₂CH₂ Me Me H H H Cl bA352 bB352 CH₂CH₂ Me Me Et H H H bA353 bB353 CH₂CH₂ Me Me H Et H H bA354 bB354 CH₂CH₂ Me Me H H Et H bA355 bB355 CH₂CH₂ Me Me H H H Et bA356 bB356 CH₂CH₂ Me Me OMe H H H bA357 bB357 CH₂CH₂ Me Me H OMe H H bA358 bB358 CH₂CH₂ Me Me H H OMe H bA359 bB359 CH₂CH₂ Me Me H H H OMe bA360 bB360 CH₂CH₂ Me Me F H H H bA361 bB361 CH₂CH₂ Me Me H F H H bA362 bB362 CH₂CH₂ Me Me H H F H bA363 bB363 CH₂CH₂ Me Me H H H F bA364 bB364 CH₂CH₂ Et Me H H H H bA365 bB365 CH₂CH₂ Et Me Me H H H bA366 bB366 CH₂CH₂ Et Me H Me H H bA367 bB367 CH₂CH₂ Et Me H H Me H bA368 bB368 CH₂CH₂ Et Me H H H Me bA369 bB369 CH₂CH₂ Et Me Cl H H H bA370 bB370 CH₂CH₂ Et Me H Cl H H bA371 bB371 CH₂CH₂ Et Me H H Cl H bA372 bB372 CH₂CH₂ Et Me H H H Cl bA373 bB373 CH₂CH₂ Et Me Et H H H bA374 bB374 CH₂CH₂ Et Me H Et H H bA375 bB375 CH₂CH₂ Et Me H H Et H bA376 bB376 CH₂CH₂ Et Me H H H Et bA377 bB377 CH₂CH₂ Et Me OMe H H H bA378 bB378 CH₂CH₂ Et Me H OMe H H bA379 bB379 CH₂CH₂ Et Me H H OMe H bA380 bB380 CH₂CH₂ Et Me H H H OMe bA381 bB381 CH₂CH₂ Et Me F H H H bA382 bB382 CH₂CH₂ Et Me H F H H bA383 bB383 CH₂CH₂ Et Me H H F H bA384 bB384 CH₂CH₂ Et Me H H H F bA385 bB385 CH₂CH₂ Allyl Me H H H H bA386 bB386 CH₂CH₂ Allyl Me Me H H H bA387 bB387 CH₂CH₂ Allyl Me H Me H H bA388 bB388 CH₂CH₂ Allyl Me H H Me H bA389 bB389 CH₂CH₂ Allyl Me H H H Me bA390 bB390 CH₂CH₂ Allyl Me Cl H H H bA391 bB391 CH₂CH₂ Allyl Me H Cl H H bA392 bB392 CH₂CH₂ Allyl Me H H Cl H bA393 bB393 CH₂CH₂ Allyl Me H H H Cl bA394 bB394 CH₂CH₂ Allyl Me Et H H H bA395 bB395 CH₂CH₂ Allyl Me H Et H H bA396 bB396 CH₂CH₂ Allyl Me H H Et H bA397 bB397 CH₂CH₂ Allyl Me H H H Et bA398 bB398 CH₂CH₂ Allyl Me OMe H H H bA399 bB399 CH₂CH₂ Allyl Me H OMe H H bA400 bB400 CH₂CH₂ Allyl Me H H OMe H bA401 bB401 CH₂CH₂ Allyl Me H H H OMe bA402 bB402 CH₂CH₂ Allyl Me F H H H bA403 bB403 CH₂CH₂ Allyl Me H F H H bA404 bB404 CH₂CH₂ Allyl Me H H F H bA405 bB405 CH₂CH₂ Allyl Me H H H F bA406 bB406 CH₂CH₂ Bzl Me H H H H bA407 bB407 CH₂CH₂ Bzl Me Me H H H bA408 bB408 CH₂CH₂ Bzl Me H Me H H bA409 bB409 CH₂CH₂ Bzl Me H H Me H bA410 bB410 CH₂CH₂ Bzl Me H H H Me bA411 bB411 CH₂CH₂ Bzl Me Cl H H H bA412 bB412 CH₂CH₂ Bzl Me H Cl H H bA413 bB413 CH₂CH₂ Bzl Me H H Cl H bA414 bB414 CH₂CH₂ Bzl Me H H H Cl bA415 bB415 CH₂CH₂ Bzl Me Et H H H bA416 bB416 CH₂CH₂ Bzl Me H Et H H bA417 bB417 CH₂CH₂ Bzl Me H H Et H bA418 bB418 CH₂CH₂ Bzl Me H H H Et bA419 bB419 CH₂CH₂ Bzl Me OMe H H H bA420 bB420 CH₂CH₂ Bzl Me H OMe H H bA421 bB421 CH₂CH₂ Bzl Me H H OMe H bA422 bB422 CH₂CH₂ Bzl Me H H H OMe bA423 bB423 CH₂CH₂ Bzl Me F H H H bA424 bB424 CH₂CH₂ Bzl Me H F H H bA425 bB425 CH₂CH₂ Bzl Me H H F H bA426 bB426 CH₂CH₂ Bzl Me H H H F bA427 bB427 CH₂CH₂ p-MeO-Bzl Me H H H H bA428 bB428 CH₂CH₂ p-MeO-Bzl Me Me H H H bA429 bB429 CH₂CH₂ p-MeO-Bzl Me H Me H H bA430 bB430 CH₂CH₂ p-MeO-Bzl Me H H Me H bA431 bB431 CH₂CH₂ p-MeO-Bzl Me H H H Me bA432 bB432 CH₂CH₂ p-MeO-Bzl Me Cl H H H bA433 bB433 CH₂CH₂ p-MeO-Bzl Me H Cl H H bA434 bB434 CH₂CH₂ p-MeO-Bzl Me H H Cl H bA435 bB435 CH₂CH₂ p-MeO-Bzl Me H H H Cl bA436 bB436 CH₂CH₂ p-MeO-Bzl Me Et H H H bA437 bB437 CH₂CH₂ p-MeO-Bzl Me H Et H H bA438 bB438 CH₂CH₂ p-MeO-Bzl Me H H Et H bA439 bB439 CH₂CH₂ p-MeO-Bzl Me H H H Et bA440 bB440 CH₂CH₂ p-MeO-Bzl Me OMe H H H bA441 bB441 CH₂CH₂ p-MeO-Bzl Me H OMe H H bA442 bB442 CH₂CH₂ p-MeO-Bzl Me H H OMe H bA443 bB443 CH₂CH₂ p-MeO-Bzl Me H H H OMe bA444 bB444 CH₂CH₂ p-MeO-Bzl Me F H H H bA445 bB445 CH₂CH₂ p-MeO-Bzl Me H F H H bA446 bB446 CH₂CH₂ p-MeO-Bzl Me H H F H bA447 bB447 CH₂CH₂ p-MeO-Bzl Me H H H F bA448 bB448 CH₂CH₂ i-Pr Me Me H H F bA449 bB449 CH₂CH₂ i-Pr Me H Me H H bA450 bB450 CH₂CH₂ i-Pr Me H H Me H bA451 bB451 CH₂CH₂ i-Pr Me H H H Me bA452 bB452 CH₂CH₂ i-Pr Me Cl H H H bA453 bB453 CH₂CH₂ i-Pr Me H Cl H H bA454 bB454 CH₂CH₂ i-Pr Me H H Cl H bA455 bB455 CH₂CH₂ i-Pr Me H H H Cl bA456 bB456 CH₂CH₂ i-Pr Me Et H H H bA457 bB457 CH₂CH₂ i-Pr Me H Et H H bA458 bB458 CH₂CH₂ i-Pr Me H H Et H bA459 bB459 CH₂CH₂ i-Pr Me H H H Et bA460 bB460 CH₂CH₂ i-Pr Me OMe H H H bA461 bB461 CH₂CH₂ i-Pr Me H OMe H H bA462 bB462 CH₂CH₂ i-Pr Me H H OMe H bA463 bB463 CH₂CH₂ i-Pr Me H H H OMe bA464 bB464 CH₂CH₂ i-Pr Me F H H H bA465 bB465 CH₂CH₂ i-Pr Me H F H H bA466 bB466 CH₂CH₂ i-Pr Me H H F H bA467 bB467 CH₂CH₂ i-Pr Me H H H F bA468 bB468 CH₂CH₂ t-Bu Me H H H H bA469 bB469 CH₂CH₂ t-Bu Me Me H H H bA470 bB470 CH₂CH₂ t-Bu Me Me Me H H bA471 bB471 CH₂CH₂ t-Bu Me H H Me H bA472 bB472 CH₂CH₂ t-Bu Me H H H Me bA473 bB473 CH₂CH₂ t-Bu Me Cl H H H bA474 bB474 CH₂CH₂ t-Bu Me H Cl H H bA475 bB475 CH₂CH₂ t-Bu Me H H Cl H bA476 bB476 CH₂CH₂ t-Bu Me H H H Cl bA477 bB477 CH₂CH₂ t-Bu Me H H H H bA478 bB478 CH₂CH₂ t-Bu Me Et H H H bA479 bB479 CH₂CH₂ t-Bu Me H Et H H bA480 bB480 CH₂CH₂ t-Bu Me H H Et H bA481 bB481 CH₂CH₂ t-Bu Me H H H Et bA482 bB482 CH₂CH₂ t-Bu Me OMe H H H bA483 bB483 CH₂CH₂ t-Bu Me H OMe H H bA484 bB484 CH₂CH₂ t-Bu Me H H OMe H bA485 bB485 CH₂CH₂ t-Bu Me H H H OMe bA486 bB486 CH₂CH₂ t-Bu Me F H H H bA487 bB487 CH₂CH₂ t-Bu Me H F H H bA488 bB488 CH₂CH₂ t-Bu Me H H F H bA489 bB489 CH₂CH₂ t-Bu Me H H H F bA490 bB490 CH₂CH₂ Ph Me H H H H bA491 bB491 CH₂CH₂ Ph Me Me H H H bA492 bB492 CH₂CH₂ Ph Me Me Me H H bA493 bB493 CH₂CH₂ Ph Me H H Me H bA494 bB494 CH₂CH₂ Ph Me H H H Me bA495 bB495 CH₂CH₂ Ph Me Cl H H H bA496 bB496 CH₂CH₂ Ph Me H Cl H H bA497 bB497 CH₂CH₂ Ph Me H H Cl H bA498 bB498 CH₂CH₂ Ph Me H H H Cl bA499 bB499 CH₂CH₂ Ph Me H H H H bA500 bB500 CH₂CH₂ Ph Me Et H H H bA501 bB501 CH₂CH₂ Ph Me H Et H H bA502 bB502 CH₂CH₂ Ph Me H H Et H bA503 bB503 CH₂CH₂ Ph Me H H H Et bA504 bB504 CH₂CH₂ Ph Me OMe H H H bA505 bB505 CH₂CH₂ Ph Me H OMe H H bA506 bB506 CH₂CH₂ Ph Me H H OMe H bA507 bB507 CH₂CH₂ Ph Me H H H OMe bA508 bB508 CH₂CH₂ Ph Me F H H H bA509 bB509 CH₂CH₂ Ph Me H F H H bA510 bB510 CH₂CH₂ Ph Me H H F H bA511 bB511 CH₂CH₂ Ph Me H H H F bA512 bB512 OCH₂ Me Me H H H H bA513 bB513 OCH₂ Me Me Me H H H bA514 bB514 OCH₂ Me Me H Me H H bA515 bB515 OCH₂ Me Me H H Me H bA516 bB516 OCH₂ Me Me H H H Me bA517 bB517 OCH₂ Me Me Cl H H H bA518 bB518 OCH₂ Me Me H Cl H H bA519 bB519 OCH₂ Me Me H H Cl H bA520 bB520 OCH₂ Me Me H H H Cl bA521 bB521 OCH₂ Me Me Et H H H bA522 bB522 OCH₂ Me Me H Et H H bA523 bB523 OCH₂ Me Me H H Et H bA524 bB524 OCH₂ Me Me H H H Et bA525 bB525 OCH₂ Me Me OMe H H H bA526 bB526 OCH₂ Me Me H OMe H H bA527 bB527 OCH₂ Me Me H H OMe H bA528 bB528 OCH₂ Me Me H H H OMe bA529 bB529 OCH₂ Me Me F H H H bA530 bB530 OCH₂ Me Me H F H H bA531 bB531 OCH₂ Me Me H H F H bA532 bB532 OCH₂ Me Me H H H F bA533 bB533 OCH₂ Et Me H H H H bA534 bB534 OCH₂ Et Me Me H H H bA535 bB535 OCH₂ Et Me H Me H H bA536 bB536 OCH₂ Et Me H H Me H bA537 bB537 OCH₂ Et Me H H H Me bA538 bB538 OCH₂ Et Me Cl H H H bA539 bB539 OCH₂ Et Me H Cl H H bA540 bB540 OCH₂ Et Me H H Cl H bA541 bB541 OCH₂ Et Me H H H Cl bA542 bB542 OCH₂ Et Me Et H H H bA543 bB543 OCH₂ Et Me H Et H H bA544 bB544 OCH₂ Et Me H H Et H bA545 bB545 OCH₂ Et Me H H H Et bA546 bB546 OCH₂ Et Me OMe H H H bA547 bB547 OCH₂ Et Me H OMe H H bA548 bB548 OCH₂ Et Me H H OMe H bA549 bB549 OCH₂ Et Me H H H OMe bA550 bB550 OCH₂ Et Me F H H H bA551 bB551 OCH₂ Et Me H F H H bA552 bB552 OCH₂ Et Me H H F H bA553 bB553 OCH₂ Et Me H H H F bA554 bB554 OCH₂ Allyl Me H H H H bA555 bB555 OCH₂ Allyl Me Me H H H bA556 bB556 OCH₂ Allyl Me H Me H H bA557 bB557 OCH₂ Allyl Me H H Me H bA558 bB558 OCH₂ Allyl Me H H H Me bA559 bB559 OCH₂ Allyl Me Cl H H H bA560 bB560 OCH₂ Allyl Me H Cl H H bA561 bB561 OCH₂ Allyl Me H H Cl H bA562 bB562 OCH₂ Allyl Me H H H Cl bA563 bB563 OCH₂ Allyl Me Et H H H bA564 bB564 OCH₂ Allyl Me H Et H H bA565 bB565 OCH₂ Allyl Me H H Et H bA566 bB566 OCH₂ Allyl Me H H H Et bA567 bB567 OCH₂ Allyl Me OMe H H H bA568 bB568 OCH₂ Allyl Me H OMe H H bA569 bB569 OCH₂ Allyl Me H H OMe H bA570 bB570 OCH₂ Allyl Me H H H OMe bA571 bB571 OCH₂ Allyl Me F H H H bA572 bB572 OCH₂ Allyl Me H F H H bA573 bB573 OCH₂ Allyl Me H H F H bA574 bB574 OCH₂ Allyl Me H H H F bA575 bB575 OCH₂ Bzl Me H H H H bA576 bB576 OCH₂ Bzl Me Me H H H bA577 bB577 OCH₂ Bzl Me H Me H H bA578 bB578 OCH₂ Bzl Me H H Me H bA579 bB579 OCH₂ Bzl Me H H H Me bA580 bB580 OCH₂ Bzl Me Cl H H H bA581 bB581 OCH₂ Bzl Me H Cl H H bA582 bB582 OCH₂ Bzl Me H H Ci H bA583 bB583 OCH₂ Bzl Me H H H Cl bA584 bB584 OCH₂ Bzl Me Et H H H bA585 bB585 OCH₂ Bzl Me H Et H H bA586 bB586 OCH₂ Bzl Me H H Et H bA587 bB587 OCH₂ Bzl Me H H H Et bA588 bB588 OCH₂ Bzl Me OMe H H H bA589 bB589 OCH₂ Bzl Me H OMe H H bA590 bB590 OCH₂ Bzl Me H H OMe H bA591 bB591 OCH₂ Bzl Me H H H OMe bA592 bB592 OCH₂ Bzl Me F H H H bA593 bB593 OCH₂ Bzl Me H F H H bA594 bB594 OCH₂ Bzl Me H H F H bA595 bB595 OCH₂ Bzl Me H H H F bA596 bB596 OCH₂ p-MeO-Bzl Me H H H H bA597 bB597 OCH₂ p-MeO-Bzl Me Me H H H bA598 bB598 OCH₂ p-MeO-Bzl Me H Me H H bA599 bB599 OCH₂ p-MeO-Bzl Me H H Me H bA600 bB600 OCH₂ p-MeO-Bzl Me H H H Me bA601 bB601 OCH₂ p-MeO-Bzl Me Cl H H H bA602 bB602 OCH₂ p-MeO-Bzl Me H Cl H H bA603 bB603 OCH₂ p-MeO-Bzl Me H H Cl H bA604 bB604 OCH₂ p-MeO-Bzl Me H H H Cl bA605 bB605 OCH₂ p-MeO-Bzl Me Et H H H bA606 bB606 OCH₂ p-MeO-Bzl Me H Et H H bA607 bB607 OCH₂ p-MeO-Bzl Me H H Et H bA608 bB608 OCH₂ p-MeO-Bzl Me H H H Et bA609 bB609 OCH₂ p-MeO-Bzl Me OMe H H H bA610 bB610 OCH₂ p-MeO-Bzl Me H OMe H H bA611 bB611 OCH₂ p-MeO-Bzl Me H H OMe H bA612 bB612 OCH₂ p-MeO-Bzl Me H H H OMe bA613 bB613 OCH₂ p-MeO-Bzl Me F H H H bA614 bB614 OCH₂ p-MeO-Bzl Me H F H H bA615 bB615 OCH₂ p-MeO-Bzl Me H H F H bA616 bB616 OCH₂ p-MeO-Bzl Me H H H F bA617 bB617 OCH₂ i-Pr Me Me H H F bA618 bB618 OCH₂ i-Pr Me H Me H H bA619 bB619 OCH₂ i-Pr Me H H Me H bA620 bB620 OCH₂ i-Pr Me H H H Me bA621 bB621 OCH₂ i-Pr Me Cl H H H bA622 bB622 OCH₂ i-Pr Me H Cl H H bA623 bB623 OCH₂ i-Pr Me H H Cl H bA624 bB624 OCH₂ i-Pr Me H H H Cl bA625 bB625 OCH₂ i-Pr Me Et H H H bA626 bB626 OCH₂ i-Pr Me H Et H H bA627 bB627 OCH₂ i-Pr Me H H Et H bA628 bB628 OCH₂ i-Pr Me H H H Et bA629 bB629 OCH₂ i-Pr Me OMe H H H bA630 bB630 OCH₂ i-Pr Me H OMe H H bA631 bB631 OCH₂ i-Pr Me H H OMe H bA632 bB632 OCH₂ i-Pr Me H H H OMe bA633 bB633 OCH₂ i-Pr Me F H H H bA634 bB634 OCH₂ i-Pr Me H F H H bA635 bB635 OCH₂ i-Pr Me H H F H bA636 bB636 OCH₂ i-Pr Me H H H F bA637 bB637 OCH₂ t-Bu Me H H H H bA638 bB638 OCH₂ t-Bu Me Me H H H bA639 bB639 OCH₂ t-Bu Me Me Me H H bA640 bB640 OCH₂ t-Bu Me H H Me H bA641 bB641 OCH₂ t-Bu Me H H H Me bA642 bB642 OCH₂ t-Bu Me Cl H H H bA643 bB643 OCH₂ t-Bu Me H Cl H H bA644 bB644 OCH₂ t-Bu Me H H Cl H bA645 bB645 OCH₂ t-Bu Me H H H Cl bA646 bB646 OCH₂ t-Bu Me H H H H bA647 bB647 OCH₂ t-Bu Me Et H H H bA648 bB648 OCH₂ t-Bu Me H Et H H bA649 bB649 OCH₂ t-Bu Me H H Et H bA650 bB650 OCH₂ t-Bu Me H H H Et bA651 bB651 OCH₂ t-Bu Me OMe H H H bA652 bB652 OCH₂ t-Bu Me H OMe H H bA653 bB653 OCH₂ t-Bu Me H H OMe H bA654 bB654 OCH₂ t-Bu Me H H H OMe bA655 bB655 OCH₂ t-Bu Me F H H H bA656 bB656 OCH₂ t-Bu Me H F H H bA657 bB657 OCH₂ t-Bu Me H H F H bA658 bB658 OCH₂ t-Bu Me H H H F bA659 bB659 OCH₂ Ph Me H H H H bA660 bB660 OCH₂ Ph Me Me H H H bA661 bB661 OCH₂ Ph Me Me Me H H bA662 bB662 OCH₂ Ph Me H H Me H bA663 bB663 OCH₂ Ph Me H H H Me bA664 bB664 OCH₂ Ph Me Cl H H H bA665 bB665 OCH₂ Ph Me H Cl H H bA666 bB666 OCH₂ Ph Me H H Cl H bA667 bB667 OCH₂ Ph Me H H H Cl bA668 bB668 OCH₂ Ph Me H H H H bA669 bB669 OCH₂ Ph Me Et H H H bA670 bB670 OCH₂ Ph Me H Et H H bA671 bB671 OCH₂ Ph Me H H Et H bA672 bB672 OCH₂ Ph Me H H H Et bA673 bB673 OCH₂ Ph Me OMe H H H bA674 bB674 OCH₂ Ph Me H OMe H H bA675 bB675 OCH₂ Ph Me H H OMe H bA676 bB676 OCH₂ Ph Me H H H OMe bA677 bB677 OCH₂ Ph Me F H H H bA678 bB678 OCH₂ Ph Me H F H H bA679 bB679 OCH₂ Ph Me H H F H bA680 bB680 OCH₂ Ph Me H H H F Physical data on compounds from table 2: Compound No.: bA214: Ref (¹), R_(t) = 6.7, n-hexane/isopropanol = 92:8 (v/v), flow rate = 0.5 ml/min, Compound No.: bA218: Ref (^(1,4)), R_(t) = 13.9, n-hexane/isopropanol = 90:10 (v/v), Flow rate = 1.0 ml/min, Compound No.: bA237: Ref (³), R_(t) = 17.4, n-hexane/isopropanol = 99:1 (v/v), flow rate = 0.3 ml/min, Compound No.: bB237: Ref (³), R_(t) = 19.9, n-hexane/isopropanol = 99:1 (v/v), flow rate = 0.3 ml/min, Compound No.: bA239: Ref (^(3,4)), R_(t) = 12.3, n-hexane/isopropanol = 90:10 (v/v), flow rate = 1.0 ml/min, Compound No.: bA406: Ref (¹), R_(t) = 7.1, n-hexane/isopropanol = 96:4 (v/v), flow rate = 0.5 ml/min. 

1. A process for preparing optically active cyclic amines of the formula (I) or salts thereof

in which A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring which has from 3 to 30 ring atoms, and may be further substituted in addition to the R¹ and NH—R⁰ radicals, R⁰, independently of R, is a (C₁-C₆)alkyl, (C₃-C₆)alkenyl or (C₃-C₁)alkynyl radical, where each of the three latter radicals may be unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, (C₁-C₄)oyloxy, (C₁-C₄)haloalkanoyloxy, aryl, aryloxy, amyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted, or (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted, R, independently of R⁰, is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₆)alkoxy, (C₁-C₆)haloalkoxy, (C₁-C₆)alkylthio, aryl which is unsubstituted or substituted, and heteroaryl which is unsubstituted or substituted, or aryl which is unsubstituted or substituted, or heteroaryl which is unsubstituted or substituted, or R⁰ and A form a ring B1 and, together with the NH group and the carbon atom which is designated with an asterisk (*) and is bonded to the NH group, are a heterocyclic ring which has from 4 to 30 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S, or R and A form a ring B2 and, together with the carbon atom which is designated with an asterisk (*) and is bonded to R, are a carbocyclic or heterocyclic ring which has from 3 to 30 ring atoms, and is optionally additionally further substituted, and which, in the case of a heterocyclic ring, contains 1, 2 or 3 further heteroatoms from the group of N, O and S, or R⁰ and R form a ring B3 and, together with the NH group and the carbon atoms designated with an asterisk (*) in each case, are a heterocyclic ring which has from 4 to 30 ring atoms, and is optionally additionally further substituted and which optionally contains 1 or 2 further heteroatoms from the group of N, O and S, or R⁰ and R and, if appropriate, A may simultaneously form two or more of the rings B1, B2 and B3 mentioned, where R and the NH—R⁰ group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the stereochemical configuration on these carbon atoms is different from the racemic configuration, which comprises converting an imine of the formula (II) or a salt thereof

where A, R⁰ and R are each as defined in formula (I) and the compound of the formula (II), with regard to the ring carbon atom marked with an asterisk (*), is present in the form of a racemic mixture or in the form of a mixture with any other isomeric ratio of the stereoisomers in question, in the presence of hydrogen or a hydrogen donor and a nonenzymatic catalyst which comprises a catalytically active optically active complex of one or more transition metals from the group of ruthenium, rhodium, palladium, iridium, osmium, platinum, iron, nickel and samarium, with organic ligands, to the compound of the formula (I).
 2. The process as claimed in claim 1, wherein the compounds (I) or salts thereof with cis configuration on the two chiral centers designated with an asterisk (*) in each case are obtained with a selectivity of from 60 to 100% in comparison to the trans configuration, one enantiomer of the cis compound being obtained with an enantioselectivity of in each case more than 20% ee based on the total content of enantiomers of the cis compound.
 3. The process as claimed in claim 1, wherein compounds of the formula (Ia) or salts thereof are prepared

in which A, together with the carbon atoms designated with an asterisk (*) in each case, is a carbocyclic or heterocyclic, saturated or unsaturated, nonaromatic ring having from 3 to 30 ring atoms and, in the case of a heterocyclic ring which has from 1 to 3 heterocyclic ring atoms from the group of N, O and S and, in addition to the R¹ and NH—R⁰ radicals is unsubstituted or further substituted by one or more radicals selected from the group consisting of halogen, hydroxy, amino, cyano, nitro, (C₁-C₄)alkyl, (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkoxycarbonyl, (C₁-C₄)alkylthio, (C₁-C₄)alkylsulfonyl, aryl and heterocyclyl, where each of the latter 8 radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₃-C₉)cycloalkyl, (C₁-C₄)alkoxy, (C₁-C₄)alkylthio and, in the case of cyclic radicals, also (C₁-C₄)alkyl and (C₁-C₄)haloalkyl, R⁰ independently of R¹, is a (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₃-C₆)alkynyl radical, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkanoyloxy, (C₁-C₄)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted, or (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted, R¹, independently of R⁰, is (C₁-C₆)alkyl, (C₂-C₆)alkenyl or (C₂-C₆)alkynyl, where each of the three latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy and (C₁-C₄)alkylthio, or aryl or heterocyclyl, where each of the 2 latter radicals is unsubstituted or substituted, where the substituents R¹ and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound (Ia) is present in the form of a stereochemically pure compound of the formula (Ia-A) or (Ia-B)

in which the general radicals are each as defined in formula (Ia), or in the form of an isomer mixture of the compounds of the formulae (Ia-A) and (Ia-B) in an isomer ratio other than the ratio of 1:1.
 4. The process as claimed in claim 1, wherein compounds of the formula (Ib) or salts thereof are prepared

in which A¹ is a direct bond or a group of the formula (CR⁶R⁷)_(n) in which n is from 1 to 6 and R⁶ and R⁷ are each independently, or, in the case that n is greater than 1, the R⁶ and R⁷ radicals are in each case independently hydrogen, (C₁-C₄)alkyl, (C₁-C₄)haloalkyl, halogen, (C₁-C₄)alkoxy or (C₁-C₄)haloalkoxy, where individual CR⁶R⁷ groups may be replaced by heteroatoms from the group of O and S, R⁰, independently of R¹, is a (C₁-C₆)alkyl or (C₂-C₆)alkenyl radical, where each of the two latter radicals is unsubstituted or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)alkylthio, (C₁-C₄)alkanoyloxy, (C₁-C₄)haloalkanoyloxy, aryl, aryloxy, aroyl, aroyloxy and heterocyclyl, where each of the latter 5 radicals is unsubstituted or substituted, or (C₃-C₉)cycloalkyl, (C₄-C₉)cycloalkenyl, aryl or heterocyclyl, where each of the latter 4 radicals is unsubstituted or substituted, R¹, independently of R⁰, is (C₁-C₆)alkyl which is unsubstitutcd or substituted by one or more radicals selected from the group consisting of halogen, cyano, (C₁-C₄)alkoxy, (C₁-C₄)haloalkoxy, (C₁-C₄)allylthio and aryl which is optionally substituted, and heterocyclyl which is optionally substituted, or aryl which is optionally substituted, or heterocyclyl which is optionally substituted, and R² is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy or CN, R³ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy or CN, R⁴ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy or CN and R⁵ is H, (C₁-C₄)alkyl, (C₁-C₃)haloalkyl, halogen, (C₁-C₃)alkoxy, (C₁-C₃)haloalkoxy or CN, where the substituents R¹ and the amino group on the two ring carbon atoms marked with an asterisk (*) in each case are arranged in cis arrangement to one another and the compound is present in the form of a stereochemically pure compound of the formula (Ib-A) or (Ib-B)

in which the general radicals are each as defined in formula (Ib), or in the form of an isomer mixture of the compounds of the formulae (Ib-A) and (Ib-B) in an isomer ratio other than the ratio of 1:1.
 5. The process as claimed in claim 1, wherein the reaction is carried out in the presence of an inert organic solvent or in substance.
 6. The process as claimed in claim 1, wherein the reaction is carried out as a catalytic hydrogenation.
 7. The process as claimed in claim 1, wherein the reaction is carried out as a catalytic transfer hydrogenation.
 8. The process as claimed in claim 7, wherein the reaction is carried out with formic acid as a hydrogen donor in the presence of a tertiary amine.
 9. The process as claimed in claim 1, wherein the imine of the formula (II) is prepared in situ from the corresponding ketone and an amine of the formula and reduced.
 10. The process as claimed in claim 2, wherein the compounds (I) or salts thereof with cis configuration on the two chiral centers designated with an asterisk (*) in each case are obtained with one enantiomer of the cis compound being obtained with an enantioselectivity of in each case more than 50% ee based on the total content of enantiomers of the cis compound. 